TW201605823A - Carboxymethyl piperidine derivative - Google Patents

Carboxymethyl piperidine derivative Download PDF

Info

Publication number
TW201605823A
TW201605823A TW103138516A TW103138516A TW201605823A TW 201605823 A TW201605823 A TW 201605823A TW 103138516 A TW103138516 A TW 103138516A TW 103138516 A TW103138516 A TW 103138516A TW 201605823 A TW201605823 A TW 201605823A
Authority
TW
Taiwan
Prior art keywords
compound
formula
added
acceptable salt
pharmacologically acceptable
Prior art date
Application number
TW103138516A
Other languages
Chinese (zh)
Other versions
TWI657082B (en
Inventor
Kazuo Shimizu
Takashi Miyagi
Kohsuke Ohno
Yasunori Ueno
Yusuke Onda
Hikaru Suzuki
Original Assignee
Kissei Pharmaceutical
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical filed Critical Kissei Pharmaceutical
Publication of TW201605823A publication Critical patent/TW201605823A/en
Application granted granted Critical
Publication of TWI657082B publication Critical patent/TWI657082B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention provides a novel compound useful in the prevention or treatment of nausea and vomiting associated with the administration of antineoplastics, the compound having an NK1 receptor-antagonizing effect, and an inhibitory effect on CYP3A4 that is attenuated to a greater extent than in aprepitant. Specifically, the present invention relates to a carboxymethyl piperidine derivative represented by formula (I) or a pharmacologically acceptable salt thereof. In the formula, ring A is a benzene ring or the like, ring B is a pyridine ring or the like, R1 is a C1-6 alkyl or C1-6 alkoxy, R2 and R3 are hydrogen atoms or methyl, and n represents an integer of from 0 to 5.

Description

羧甲基哌啶衍生物 Carboxymethyl piperidine derivative

本發明係關於一種作為醫藥品較有用之羧甲基哌啶衍生物。 The present invention relates to a carboxymethylpiperidine derivative which is useful as a pharmaceutical.

進而詳細而言，本發明係關於一種具有P物質/神經激肽1(NK1)受體拮抗作用而作為伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐(CINV)等之預防或治療劑較有用的羧甲基哌啶衍生物或其藥理學上容許之鹽。 More specifically, the present invention relates to a prophylactic or therapeutic agent for nausea and vomiting (CINV) which is caused by administration of a substance P/neurokinin 1 (NK 1 ) receptor antagonist as a concomitant anti-neoplastic agent. A more useful carboxymethylpiperidine derivative or a pharmacologically acceptable salt thereof.

CINV係藉由存在於延髓外側網狀體之嘔吐中樞受到刺激而表現。NK1受體存在於延髓之最後區及孤束核，認為NK1受體與嘔吐強烈相關。藉由投予抗惡性腫瘤劑，自存在於消化道之腸親鉻(EC)細胞之血清素分泌亢進，血清素經由消化道之5-羥色胺3(5-HT3，5-Hydroxytryptamine3)受體而直接刺激嘔吐中樞。又，藉由血清素經由存在於第四腦室最後區之化學感受器觸發帶(CTZ，chemoreceptor trigger zone)而刺激嘔吐中樞，而表現噁心及嘔吐。P物質與血清素同樣存在於消化道之EC細胞內，且藉由投予抗惡性腫瘤劑而被促進分泌。近年來，明瞭P物質係經由存在於CTZ之NK1受體而誘發嘔吐，或者藉由與中樞神經系統之NK1受體結合而誘發嘔吐，NK1受體作為止吐劑之開發目標而備受關注(非專利文獻1)。 CINV is expressed by stimulation of the vomiting center present in the medullary reticular body. The NK 1 receptor is present in the last region of the medulla oblongata and the solitary tract nucleus, and the NK 1 receptor is strongly associated with vomiting. By administering an anti-malignant agent, serotonin is secreted from intestinal chromium (EC) cells present in the digestive tract, and serotonin is passed through the gastrointestinal serotonin 3 (5-HT 3 , 5-Hydroxytryptamine 3 ) The body directly stimulates the vomiting center. Further, sputum is stimulated by serotonin via a chemoreceptor trigger zone (CTZ) present in the final region of the fourth ventricle, and nausea and vomiting are exhibited. Substance P is present in the EC cells of the digestive tract as well as serotonin, and is promoted by administration of an anti-malignant agent. In recent years, it has been clarified that substance P induces vomiting via the NK 1 receptor present at CTZ, or induces vomiting by binding to the NK 1 receptor of the central nervous system, and NK 1 receptor is prepared as an antiemetic target. Attention is concerned (Non-Patent Document 1).

阿瑞吡坦(Aprepitant)係被批准為針對伴隨抗惡性腫瘤 劑投予所產生之噁心及嘔吐之預防劑的世界首個選擇性NK1受體拮抗劑。認為阿瑞吡坦之作用機制係選擇性地抑制作為CINV之誘發路徑之一的P物質與中樞神經系統NK1受體之結合，而預防CINV。阿瑞吡坦係作為CINV之預防劑而被銷售(非專利文獻2)。 Aprepitant is approved as the world's first selective NK 1 receptor antagonist against prophylactic agents for nausea and vomiting associated with the administration of anti-malignant agents. It is considered that the mechanism of action of aprepitant selectively inhibits the binding of substance P, which is one of the induction pathways of CINV, to the central nervous system NK 1 receptor, and prevents CINV. Aprestatin is marketed as a prophylactic agent for CINV (Non-Patent Document 2).

已知阿瑞吡坦係藉由細胞色素P450(CYP)3A4而代謝。又，亦已知阿瑞吡坦具有對CYP3A4之劑量依存性抑制作用、CYP3A4之誘導作用及CYP2C9之誘導作用。因此，阿瑞吡坦有與抑制或誘導CYP3A4之藥劑、或藉由CYP3A4或CYP2C9而代謝之藥劑引起藥物間相互作用的可能性。例如有如下報告：存在因阿瑞吡坦之CYP3A4抑制作用而抑制***之代謝之情形，***於與阿瑞吡坦併用之情形時必須調整劑量(非專利文獻3)。因此，於使用阿瑞吡坦時，必須充分注意基於阿瑞吡坦之CYP3A4抑制作用之藥物間相互作用。 Aprepitant is known to be metabolized by cytochrome P450 (CYP) 3A4. Further, it is also known that aprepitant has a dose-dependent inhibitory effect on CYP3A4, an induction of CYP3A4, and an induction of CYP2C9. Therefore, aprepitant has the possibility of causing drug-drug interaction with an agent that inhibits or induces CYP3A4, or an agent that is metabolized by CYP3A4 or CYP2C9. For example, there is a report that the metabolism of dexamethasone is inhibited by the inhibition of CYP3A4 by aprepitant, and the dose of dexamethasone must be adjusted when it is used in combination with aprepitant (Non-Patent Document 3). Therefore, when using aprepitant, it is necessary to pay sufficient attention to the drug-drug interaction based on the inhibitory effect of aprepitant on CYP3A4.

根據上述，業界期待於CINV之預防或治療中藥物間相互作用較少之新穎之NK1受體拮抗劑。 In light of the above, the industry expects novel NK 1 receptor antagonists with less interaction between drugs in the prevention or treatment of CINV.

已知有卡索吡坦(Casopitant)、奈妥吡坦(Netupitant)、依洛吡坦(Ezlopitant)、羅拉吡坦(Rolapitant)、維替吡坦(Vestipitant)及沃伏吡坦(Vofopitant)等具有NK1受體拮抗作用之化合物。然而，報告有卡索吡坦具有對CYP3A4之抑制作用及由此所引起之藥物間相互作用(非專利文獻4)。卡索吡坦於美國及歐洲作為針對伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防劑而實施了臨床試驗，但於申請後開發被中止。奈妥吡坦作為針對伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防劑而正在開發，但報告有其具有對CYP3A4之抑制作用及由此所引起之藥物間相互作用(非專利文獻5)。依洛吡坦於美國作為針對伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防劑而實施了臨床試 驗，但其開發被中止。沃伏吡坦於歐洲作為針對伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防劑而實施了臨床試驗，但其開發被中止。於上述化合物中，結果開發中止之之化合物較多。該等均未實現市售。 Known as Casopitant, Netupitant, Ezlopitant, Rolapitant, Vestipitant, Vofopitant, etc. A compound having NK 1 receptor antagonism. However, it has been reported that carbopyramine has an inhibitory effect on CYP3A4 and a drug-induced interaction caused thereby (Non-Patent Document 4). Cassoprotan was clinically tested in the United States and Europe as a preventive agent against nausea and vomiting caused by the administration of anti-malignant agents, but development was suspended after the application. Nectrolide is being developed as a prophylactic agent against nausea and vomiting caused by administration of an anti-malignant agent, but it has been reported to have an inhibitory effect on CYP3A4 and a drug-induced interaction thereof (Non-Patent Literature) 5). Iloprotan was administered in the United States as a preventive agent against nausea and vomiting caused by administration of an anti-malignant agent, but its development was discontinued. Wolfafatin was clinically tested in Europe as a preventive agent against nausea and vomiting caused by administration of anti-malignant agents, but its development was discontinued. Among the above compounds, the number of compounds in which the development was discontinued was large. None of these are commercially available.

專利文獻1~16中記載有主張具有NK1受體拮抗作用之吡啶衍生物。又，專利文獻17及18中記載有吡啶衍生物之前驅藥。然而，上述文獻中並未記載本案發明之羧甲基哌啶衍生物。 Patent Documents 1 to 16 disclose pyridine derivatives which have an NK 1 receptor antagonistic action. Further, Patent Documents 17 and 18 describe a pyridine derivative precursor drug. However, the carboxymethylpiperidine derivatives of the present invention are not described in the above documents.

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

專利文獻1：美國專利第6,479,483號說明書 Patent Document 1: US Patent No. 6,479,483

專利文獻2：美國專利第6,770,637號說明書 Patent Document 2: US Patent No. 6,770,637

專利文獻3：美國專利第7,939,533號說明書 Patent Document 3: US Patent No. 7,939,533

專利文獻4：歐洲專利第1,103,545號說明書 Patent Document 4: European Patent No. 1,103,545

專利文獻5：美國專利第7,211,579號說明書 Patent Document 5: US Patent No. 7,211,579

專利文獻6：美國專利申請案公開第2006/0030600號說明書 Patent Document 6: US Patent Application Publication No. 2006/0030600

專利文獻7：美國專利第6,576,762號說明書 Patent Document 7: U.S. Patent No. 6,576,762

專利文獻8：美國專利第6,225,316號說明書 Patent Document 8: U.S. Patent No. 6,225,316

專利文獻9：美國專利第7,683,056號說明書 Patent Document 9: U.S. Patent No. 7,683,056

專利文獻10：美國專利第8,344,005號說明書 Patent Document 10: U.S. Patent No. 8,344,005

專利文獻11：國際公開第2011/054773號 Patent Document 11: International Publication No. 2011/054773

專利文獻12：美國專利申請案公開第2007/0071813號說明書 Patent Document 12: US Patent Application Publication No. 2007/0071813

專利文獻13：美國專利申請案公開第2003/0083345號說明書 Patent Document 13: US Patent Application Publication No. 2003/0083345

專利文獻14：美國專利申請案公開第2003/0004157號說明書 Patent Document 14: US Patent Application Publication No. 2003/0004157

專利文獻15：美國專利第6,849,624號說明書 Patent Document 15: US Patent No. 6,849,624

專利文獻16：美國專利第6,297,375號說明書 Patent Document 16: US Patent No. 6,297,375

專利文獻17：美國專利第6,593,472號說明書 Patent Document 17: U.S. Patent No. 6,593,472

專利文獻18：美國專利第8,426,450號說明書 Patent Document 18: US Patent No. 8,426,450

[非專利文獻] [Non-patent literature]

非專利文獻1：P. J. Hesketh等人，「European Journal of Cancer」，2003年，第39卷，p.1074-1080 Non-Patent Document 1: P. J. Hesketh et al., "European Journal of Cancer", 2003, Vol. 39, p. 1074-1080

非專利文獻2：Toni M. Dando等人，「Drugs」，2004年，第64卷，第7號，p.777-794 Non-Patent Document 2: Toni M. Dando et al., "Drugs", 2004, Vol. 64, No. 7, p. 777-794

非專利文獻3：Jacqueline B. McCrea等人，「CLINICAL PHARMACOLOGY & THERAPEUTICS」，2003年，第74卷，第1號，p.17-24 Non-Patent Document 3: Jacqueline B. McCrea et al., "CLINICAL PHARMACOLOGY & THERAPEUTICS", 2003, Vol. 74, No. 1, p. 17-24

非專利文獻4：Stefano Zamuner等人，「British Journal of Clinical Pharmacology」，2010年，第70卷，第4號，p.537-546 Non-Patent Document 4: Stefano Zamuner et al., "British Journal of Clinical Pharmacology", 2010, Vol. 70, No. 4, p. 537-546

非專利文獻5：Corinna Lanzarotti等人，「Support Care Cancer」，2013年，第21卷，第10號，p.2783-2791 Non-Patent Document 5: Corinna Lanzarotti et al., "Support Care Cancer", 2013, Vol. 21, No. 10, p. 2783-2791

本發明之課題在於提供一種新穎化合物，其具有NK1受體拮抗作用，與阿瑞吡坦相比CYP3A4之抑制作用得到減弱，對伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防或治療較為有用。較佳為本發明之課題在於提供一種中樞轉移性及藥效之持續性優異之上述化合物。 The object of the present invention is to provide a novel compound which has NK 1 receptor antagonism, which has attenuated the inhibition of CYP3A4 compared with aprepitant, and prevents nausea and vomiting caused by administration of an anti-malignant agent. Treatment is more useful. It is a preferred object of the present invention to provide the above-mentioned compound which is excellent in the continuity of the central transfer and the persistence of the drug.

本發明係關於下述式(I)所表示之化合物或其藥理學上容許之鹽。 The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof.

即，本發明係關於下述[1]~[12]等。 That is, the present invention relates to the following [1] to [12] and the like.

[1]一種化合物或其藥理學上容許之鹽，該化合物係以式(I)表示： [1] A compound or a pharmacologically acceptable salt thereof, which is represented by the formula (I):

[式中，環A為式： [wherein, ring A is of the formula:

所表示之基；環B為式： The base represented; ring B is of the formula:

所表示之基；(其中，標記(＊)之鍵為與式：[化4] The base represented; (where the key of the mark (*) is the formula: [Chemical 4]

之鍵結部位；標記(＊＊)之鍵為與環A之鍵結部位；標記(＊＊＊)之鍵表示與式： The bonding part; the key of the mark (**) is the bonding part with the ring A; the key of the mark (***) is expressed by the formula:

之鍵結部位)；R1為C1-6烷基或C1-6烷氧基；R2及R3分別獨立為氫原子或甲基；n為0、1、2、3、4或5]。 a bonding site); R 1 is a C 1-6 alkyl group or a C 1-6 alkoxy group; and R 2 and R 3 are each independently a hydrogen atom or a methyl group; n is 0, 1, 2, 3, 4 or 5].

[2]如上述[1]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以式(Ia)表示： [2] The compound according to the above [1] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the formula (Ia):

[式中，環A、R1、及n為與上述[1]相同之含義；環Bb為式：[化7] [wherein, Ring A, R 1 , and n have the same meanings as the above [1]; Ring B b is of the formula: [Chem. 7]

所表示之基；(式中，標記(＊)之鍵為與式： The base represented; (where the key of the mark (*) is the formula:

之鍵結部位；(＊＊)及(＊＊＊)為與上述[1]相同之含義)]。 The bonding portion; (**) and (***) have the same meaning as the above [1])].

[3]如上述[2]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以式(Ib)表示： [3] The compound of the above [2] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the formula (Ib):

[式中，環A及環Bb為與上述[2]相同之含義；(其中，標記(＊)之鍵為與式： [wherein, ring A and ring B b have the same meaning as the above [2]; (wherein the bond of the mark (*) is a formula:

之鍵結部位； (＊＊)及(＊＊＊)為與上述[2]相同之含義)；R1a、R1b、R1c、R1d及R1e分別獨立為氫原子、甲基或甲氧基]。 The bonding sites; (**) and (***) have the same meaning as the above [2]; R 1a , R 1b , R 1c , R 1d and R 1e are each independently a hydrogen atom, a methyl group or a methyl group. Oxy].

[4]如上述[1]記載之化合物或其藥理學上容許之鹽，其中，環B係以下述式表示： [4] The compound of the above [1] or a pharmacologically acceptable salt thereof, wherein the ring B is represented by the following formula:

(式中，(＊)、(＊＊)及(＊＊＊)為與上述[1]相同之含義)。 (wherein, (*), (**), and (***) have the same meaning as the above [1]).

[5]如上述[4]記載之化合物或其藥理學上容許之鹽，其中，R1為甲基，且n為0或1。 [5] The compound according to the above [4], wherein R 1 is a methyl group, and n is 0 or 1, or a pharmacologically acceptable salt thereof.

[6]如上述[2]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以下述式表示： [6] The compound according to the above [2] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the following formula:

[7]如上述[2]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以下述式表示：[化13] [7] The compound according to the above [2] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the following formula: [Chem. 13]

[8]如上述[2]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以下述式表示： [8] The compound according to the above [2] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the following formula:

[9]如上述[2]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以下述式表示： [9] The compound according to the above [2] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the following formula:

[10]如上述[1]記載之化合物或其藥理學上容許之鹽，其中，該化合物係以下述式表示： [化16] [10] The compound according to the above [1] or a pharmacologically acceptable salt thereof, wherein the compound is represented by the following formula: [Chem. 16]

[11]一種醫藥組成物，其含有如上述[1]至[10]中任一項記載之化合物或其藥理學上容許之鹽作為有效成分。 [11] A pharmaceutical composition comprising the compound according to any one of the above [1] to [10] or a pharmacologically acceptable salt thereof as an active ingredient.

[12]如上述[11]記載之醫藥組成物，其係用於預防伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之醫藥組成物。 [12] The pharmaceutical composition according to the above [11], which is a pharmaceutical composition for preventing nausea and vomiting caused by administration of an anti-neoplastic agent.

本發明之化合物具有優異之NK1受體拮抗作用。又，本發明之化合物之CYP3A4之抑制作用與阿瑞吡坦相比得到減弱。進而，本發明之較佳之化合物之中樞轉移性及藥效之持續性優異。因此，本發明之化合物或其藥理學上容許之鹽作為伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防或治療劑較為有用。 The compounds of the invention have excellent NK 1 receptor antagonism. Further, the inhibitory action of CYP3A4 of the compound of the present invention is attenuated as compared with aprepitant. Further, preferred compounds of the present invention are excellent in central metastaticity and drug efficacy. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a prophylactic or therapeutic agent for nausea and vomiting which is caused by administration of an anti-malignant agent.

圖1表示試驗例6之對順鉑誘發急性及遲發性嘔吐反應之作用。圖中，柱狀圖自左起分別表示急性期(Acute)之對照群組(Control)、實施例1之化合物3mg/kg靜脈內投予群組(Ex.No 1，3mg/kg，iv)、及實施例1之化合物1mg/kg經口投予群組(Ex.No 1，1mg/kg，po)之值、以及遲發期(Delayed)之對照群組、實施例1之化合物3mg/kg靜脈內投予群組、及實施例1之化合物1mg/kg經口投予群組之值。縱軸表示乾嘔及嘔吐之表現次數(Retches+Vomites)(對照群組5例之平均值+標 準誤差、靜脈內投予群組5例之平均值+標準誤差、及經口投予群組2例之平均值)。 Figure 1 shows the effect of Test Example 6 on cisplatin-induced acute and delayed vomiting. In the figure, the histograms represent the acute control group (Control) from the left, and the compound of Example 1 3 mg/kg intravenous administration group (Ex. No 1, 3 mg/kg, iv). And the compound of Example 1 1 mg/kg orally administered to the group (Ex. No 1, 1 mg/kg, po), and the delayed control group, the compound of Example 1 3 mg/kg/ The values of the oral administration group of kg and the 1 mg/kg of the compound of Example 1 were orally administered to the group. The vertical axis indicates the number of performances of retching and vomiting (Retches+Vomites) (average of 5 cases in the control group + standard) The quasi-error, the mean value of 5 cases of intravenous administration group + standard error, and the average of 2 cases of oral administration group).

於本發明中，各用語只要未特別預先說明則具有以下之含義。 In the present invention, the terms have the following meanings unless otherwise specified.

所謂「C1-6烷基」係指碳數1~6之直鏈狀或支鏈狀之烷基，例如可列舉：甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基。所謂「C1-6烷氧基」係指碳數1~6之直鏈狀或支鏈狀之烷氧基，例如可列舉：甲氧基、乙氧基、丙氧基、異丙氧基。 The "C 1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. Base, second butyl, tert-butyl. The "C 1-6 alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. .

於本發明之式(I)所表示之化合物中，R1表示哌啶環上之取代基。 In the compound represented by the formula (I) of the present invention, R 1 represents a substituent on the piperidine ring.

以下，更詳細地說明本發明。 Hereinafter, the present invention will be described in more detail.

於本發明之式(I)所表示之化合物中存在1個或1個以上之不對稱碳原子之情形時，本發明亦包含各個不對稱碳原子為R配置之化合物、各個不對稱碳原子為S配置之化合物及該等之任意組合之化合物。又，該等之外消旋化合物、外消旋混合物、單一之對映體及非對映體混合物亦包含於本發明之範圍中。於本發明之式(I)所表示之化合物中存在順反異構物之情形時，本發明亦包含其順反異構物之任一者。 In the case where one or more asymmetric carbon atoms are present in the compound represented by the formula (I) of the present invention, the present invention also includes a compound in which each asymmetric carbon atom is R, and each asymmetric carbon atom is A compound of the S configuration and a compound of any combination thereof. Further, such racemic compounds, racemic mixtures, single enantiomers and diastereomeric mixtures are also included in the scope of the invention. In the case where a cis-trans isomer is present in the compound represented by the formula (I) of the present invention, the present invention also encompasses any of its cis-trans isomers.

於本發明中，立體化學之決定亦可藉由該技術領域中所周知之方法而進行(例如參照「特論NMR立體化學」(講談社)，2012年發行，59頁)。 In the present invention, the determination of stereochemistry can also be carried out by a method known in the art (for example, see "Special NMR Stereochemistry" (Kodansha), issued in 2012, page 59).

本發明之式(I)所表示之化合物亦可視需要按照常法而製成其藥理學上容許之鹽。作為此種鹽，可列舉酸加成鹽或與鹼之鹽。 The compound represented by the formula (I) of the present invention can also be prepared into a pharmacologically acceptable salt according to a usual method as needed. As such a salt, an acid addition salt or a salt with a base can be mentioned.

作為酸加成鹽，可列舉：與鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等無機酸之酸加成鹽；與甲酸、乙酸、三氟乙酸、甲磺酸、苯磺酸、對甲苯磺酸、丙酸、檸檬酸、丁二酸、酒石酸、反丁烯二酸、丁酸、草酸、丙二酸、馬來酸、乳酸、蘋果酸、碳酸、苯甲酸、麩胺酸、天冬胺酸等有機酸之酸加成鹽。 Examples of the acid addition salt include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and benzenesulfonic acid. , p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid An acid addition salt of an organic acid such as aspartic acid.

作為與鹼之鹽，可列舉：鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽等與無機鹼之鹽；與N-甲基-D-還原葡糖胺、N,N'-二苄基乙二胺、三乙胺、哌啶、啉、吡咯啶、精胺酸、離胺酸、膽鹼等有機鹼之鹽。 Examples of the salt with a base include a salt of a lithium salt, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, and the like; and N-methyl-D-reduced glucosamine, N, N'-dibenzyl Ethylenediamine, triethylamine, piperidine, a salt of an organic base such as a porphyrin, pyrrolidine, arginine, lysine or choline.

於本發明中，藥理學上容許之鹽中亦包含與水或乙醇等作為醫藥品而容許之溶劑之溶劑合物。 In the present invention, the pharmacologically acceptable salt also contains a solvate which is a solvent which is allowed as a pharmaceutical product such as water or ethanol.

於本發明之式(I)所表示之化合物之一實施樣態中，n為0、1或2。 In one embodiment of the compound represented by the formula (I) of the present invention, n is 0, 1, or 2.

本發明之式(I)所表示之化合物例如可按照以下方法或依據其之方法、或文獻記載之方法或依據其之方法進行製造。 The compound represented by the formula (I) of the present invention can be produced, for example, by the following method or a method according to the method, or a method described in the literature or a method according to the method.

[流程1] [Flow 1]

式中之L1及L2分別獨立為氯原子、溴原子、碘原子、三氟甲磺醯氧基等脫離基，PG1為保護基，環A、環B、R1、R2、R3及n具有與上述相同之含義。 In the formula, L 1 and L 2 are each independently a leaving group such as a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group, and PG 1 is a protective group, and ring A, ring B, R 1 , R 2 and R are respectively 3 and n have the same meanings as described above.

步驟1(Process 1) Step 1 (Process 1)

亦可於惰性溶劑中、鹼及鈀觸媒存在下使化合物(2)與化合物(3)進行偶合反應，而製造化合物(4)。 Compound (2) can also be produced by coupling a compound (2) with a compound (3) in an inert solvent in the presence of a base and a palladium catalyst.

步驟2(Process 2) Step 2 (Process 2)

亦可於惰性溶劑中、鹼存在下使化合物(4)與化合物(5)進行縮合反應，藉此製造化合物(6)。 Compound (6) can also be produced by subjecting compound (4) to compound (5) by a condensation reaction in an inert solvent in the presence of a base.

步驟3(Process 3) Step 3 (Process 3)

亦可於惰性溶劑中、鹼存在下或不存在下使化合物(6)與化合物(7)進行反應而脫保護，藉此製造化合物(I)。作為惰性溶劑，例如可列舉：N,N-二甲基甲醯胺、N-甲基吡咯啶酮、二甲基亞碸、二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷、苯、甲苯、二甲苯、該等之混合溶劑。作為鹼，例如可列舉：碳酸鉀、碳酸鈉、碳酸銫、氫氧化鈉、氫氧化鉀、氫氧化鋰、氟化鉀、氟化銫、三乙胺、吡啶、N,N-二異丙基乙基胺、2,6-二甲基吡啶、1,8-二氮雜雙環[5,4,0]-7-十一烯。反應溫度通常為0℃至回流溫度。反應時間係根據所使用之原料物質或溶劑、反應溫度等而異，通常為30分鐘~7天。上述反應亦可使用微波反應裝置(Biotage)進行。於使用微波反應裝置進行反應之情形時，可於壓力範圍：1~30bar、輸出區域：1~400W、反應溫度：室溫~300℃、 反應時間：1分鐘~1天之條件下進行反應，但根據所使用之原料物質、溶劑、及機種等而異。 Compound (I) can also be produced by reacting compound (6) with compound (7) in an inert solvent in the presence or absence of a base to deprotect. Examples of the inert solvent include N,N-dimethylformamide, N-methylpyrrolidone, dimethyl hydrazine, diethyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, benzene, toluene, xylene, a mixed solvent of these. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride, cesium fluoride, triethylamine, pyridine, and N,N-diisopropyl. Ethylamine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene. The reaction temperature is usually from 0 ° C to the reflux temperature. The reaction time varies depending on the starting material or solvent to be used, the reaction temperature, etc., and is usually from 30 minutes to 7 days. The above reaction can also be carried out using a microwave reaction apparatus (Biotage). When the reaction is carried out using a microwave reaction apparatus, the reaction can be carried out under the conditions of a pressure range of 1 to 30 bar, an output area of 1 to 400 W, a reaction temperature of room temperature to 300 ° C, and a reaction time of 1 minute to 1 day. However, it varies depending on the raw materials, solvents, and models used.

[流程2] [Process 2]

式中之PG1、PG2為保護基，R1、R2及n具有與上述相同之含義。 In the formula, PG 1 and PG 2 are a protecting group, and R 1 , R 2 and n have the same meanings as described above.

步驟4(Process 4) Step 4 (Process 4)

亦可於惰性溶劑中、鹼存在下使化合物(9)與化合物(8)進行烯烴化反應而製造化合物(10)。作為惰性溶劑，例如可列舉：N,N-二甲基甲醯胺、N-甲基吡咯啶酮、二甲基亞碸、二***、四氫呋喃、1,4-二烷、1,2-二甲氧基乙烷、苯、甲苯、二甲苯、該等之混合溶劑。作為鹼，例如可列舉：氫化鈉、甲醇鈉、碳酸鉀、碳酸銫、第三丁醇鉀、三乙胺、N,N-二異丙基乙基胺、1,8-二氮雜雙環[5,4,0]-7-十一烯。反應溫度通常為-78℃至回流溫度。反應時間係根據所使用之原料物質或溶劑、反應溫度等而異，通常為30分鐘~7天。反應亦可使用微波反應裝置(Biotage)進行。 Compound (10) can also be produced by subjecting compound (9) to compound (8) in an olefination reaction in an inert solvent in the presence of a base. Examples of the inert solvent include N,N-dimethylformamide, N-methylpyrrolidone, dimethyl hydrazine, diethyl ether, tetrahydrofuran, and 1,4-two. Alkane, 1,2-dimethoxyethane, benzene, toluene, xylene, a mixed solvent of these. Examples of the base include sodium hydride, sodium methoxide, potassium carbonate, cesium carbonate, potassium t-butoxide, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[ 5,4,0]-7-undecene. The reaction temperature is usually -78 ° C to reflux temperature. The reaction time varies depending on the starting material or solvent to be used, the reaction temperature, etc., and is usually from 30 minutes to 7 days. The reaction can also be carried out using a microwave reaction apparatus (Biotage).

步驟5(Process 5) Step 5 (Process 5)

亦可藉由接觸還原法等使化合物(10)還原烯烴而脫保護，藉此製造化合物(7a)。接觸還原法例如可藉由於氫氣環境下、於溶劑中對化合物(10)使用觸媒而進行。作為可使用之溶劑，例如可列舉：甲醇、乙醇、乙酸乙酯、四氫呋喃、乙酸。作為觸媒，例如可列舉：鈀碳粉末、銠碳粉末、鉑碳粉末、經釩摻雜之鉑碳粉末。反應溫度通常為室溫至回流溫度。反應時間係根據所使用之原料物質或溶劑、反應溫度等而異，通常為30分鐘~7天。 The compound (7a) can also be produced by deprotecting the compound (10) by a contact reduction method or the like to reduce the olefin. The contact reduction method can be carried out, for example, by using a catalyst for the compound (10) in a solvent under a hydrogen atmosphere. Examples of the solvent that can be used include methanol, ethanol, ethyl acetate, tetrahydrofuran, and acetic acid. Examples of the catalyst include palladium carbon powder, ruthenium carbon powder, platinum carbon powder, and vanadium-doped platinum carbon powder. The reaction temperature is usually from room temperature to reflux temperature. The reaction time varies depending on the starting material or solvent to be used, the reaction temperature, etc., and is usually from 30 minutes to 7 days.

上述所示之流程係用以製造本發明之式(I)所表示之化合物或其製造中間物之方法之例示。上述流程可進行各種改變而成為從業者可容易理解之流程。 The above-described procedures are exemplified for the production of the compound represented by the formula (I) of the present invention or a process for producing the same. The above process can be changed to become a process that can be easily understood by practitioners.

於上述所示之流程中，於根據官能基之種類而需要保護基之情形時，亦可按照常法將導入及脫離之操作適當組合而實施。 In the above-described scheme, when a protecting group is required depending on the kind of the functional group, the operations of introducing and removing may be appropriately combined in accordance with a usual method.

本發明之式(I)所表示之化合物及其製造中間物亦可視需要藉由作為該技術領域之從業者所周知之單離及純化手段的溶劑萃取、晶析、再結晶、層析法、製備高效液相層析法等進行單離及純化。 The compound represented by the formula (I) of the present invention and an intermediate thereof can also be subjected to solvent extraction, crystallization, recrystallization, chromatography, as well as separation and purification means well known to those skilled in the art. Preparation by high performance liquid chromatography or the like for isolation and purification.

本發明之化合物由於具有優異之NK1受體拮抗作用，故而亦可用作介存NK1受體之各種疾病之預防或治療劑。例如本發明之化合物作為止吐劑較為有用，尤其是作為伴隨抗惡性腫瘤劑(例如順鉑)投予所產生之消化系統症狀(例如噁心及嘔吐)之預防劑較為有用。本發明之較佳化合物不僅對伴隨抗惡性腫瘤劑投予所產生之急性期之噁心及嘔吐有用，亦對伴隨抗惡性腫瘤劑投予所產生之遲發期之噁心及嘔吐有用。 Since the compound of the present invention has excellent NK 1 receptor antagonism, it can also be used as a prophylactic or therapeutic agent for various diseases in which the NK 1 receptor is present. For example, the compound of the present invention is useful as an antiemetic, and is particularly useful as a prophylactic agent for digestive symptoms (e.g., nausea and vomiting) which are caused by administration of an anti-malignant agent (e.g., cisplatin). The preferred compounds of the present invention are useful not only for nausea and vomiting in the acute phase associated with administration of anti-neoplastic agents, but also for nausea and vomiting associated with delayed onset of administration of anti-neoplastic agents.

又，作為一實施樣態，本發明之化合物由於具有優異之NK1受體拮抗作用，故而亦可用作例如術後之噁心及嘔吐(PONV)、伴 隨放射線療法所產生之噁心及嘔吐、嗎啡誘發嘔吐、或暈動病之預防劑、或精神***症、社交焦慮症、焦慮及抑鬱症、酒精依賴症、急躁性腸症候群、潰瘍性結腸炎、咳嗽、哮喘、異位性皮膚炎、牛皮癬、瘙癢症、疼痛、偏頭痛、耳鳴、攝護腺增生、膀胱過動症、或尿失禁之治療劑。 Further, as an embodiment, the compound of the present invention can also be used, for example, as postoperative nausea and vomiting (PONV), nausea and vomiting accompanying radiation therapy, morphine, because of its excellent NK 1 receptor antagonism. Prophylactic agents for inducing vomiting or motion sickness, or schizophrenia, social anxiety, anxiety and depression, alcohol dependence, irritable bowel syndrome, ulcerative colitis, cough, asthma, atopic dermatitis, psoriasis A therapeutic agent for pruritus, pain, migraine, tinnitus, prostate hyperplasia, overactive bladder, or urinary incontinence.

本發明之醫藥組成物可根據用法而使用各種劑型者。作為此種劑型，例如可列舉：散劑、顆粒劑、細粒劑、乾糖漿劑、錠劑、膠囊劑、注射劑、液劑、軟膏劑、栓劑、貼附劑，可經口投予或非經口投予。 The pharmaceutical composition of the present invention can be used in various dosage forms depending on the usage. Examples of such a dosage form include powders, granules, fine granules, dry syrups, troches, capsules, injections, solutions, ointments, suppositories, and patches, which can be administered orally or non-menstrually. Oral injection.

本發明之醫藥組成物係使用式(I)所表示之化合物或其藥理學上容許之鹽、及至少1種醫藥品添加物而製備。該等醫藥組成物亦可藉由如下方式製備：根據其劑型藉由製劑學上公知之方法與適宜之賦形劑、崩解劑、結合劑、潤滑劑、稀釋劑、緩衝劑、等張劑、防腐劑、濕潤劑、乳化劑、分散劑、穩定化劑、溶解助劑等醫藥品添加物適當進行混合、稀釋或溶解。 The pharmaceutical composition of the present invention is prepared by using the compound represented by the formula (I) or a pharmacologically acceptable salt thereof, and at least one pharmaceutical additive. The pharmaceutical compositions can also be prepared by a method known in the art and a suitable excipient, disintegrating agent, binding agent, lubricant, diluent, buffer, isotonic agent according to the dosage form thereof. The pharmaceutical additives such as preservatives, wetting agents, emulsifiers, dispersing agents, stabilizing agents, and dissolution aids are appropriately mixed, diluted, or dissolved.

於將本發明之醫藥組成物用於預防或治療之情形時，作為其有效成分之本發明之式(I)所表示之化合物或其藥理學上容許之鹽之投予量係根據患者之年齡、性別、體重、疾病及治療之程度等而適當決定。關於對成人之投予量，於經口投予之情形時，例如亦可於1~1000mg/天、0.1~500mg/天、0.1~100mg/天、或0.1~50mg/天之範圍內決定，亦可將1天之投予量分為1次、2次、3次或4次而投予。又，於非經口投予之情形時，例如亦可於1~1000mg/天、0.1~500mg/天、0.1~100mg/天、或0.1~50mg/天之範圍內決定，亦可將1天之投予量分為1次、2次、3次或4次而投予。 When the pharmaceutical composition of the present invention is used for the prevention or treatment, the administration amount of the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient thereof is based on the age of the patient. The gender, weight, disease, and degree of treatment are appropriately determined. The dosage of the adult is determined in the case of oral administration, for example, in the range of 1 to 1000 mg/day, 0.1 to 500 mg/day, 0.1 to 100 mg/day, or 0.1 to 50 mg/day. It is also possible to divide the dose for one day into one, two, three or four times. Moreover, in the case of non-oral administration, for example, it may be determined within the range of 1 to 1000 mg/day, 0.1 to 500 mg/day, 0.1 to 100 mg/day, or 0.1 to 50 mg/day, or one day. The dose is divided into 1, 2, 3 or 4 times and administered.

於將本發明之醫藥組成物用作伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防用醫藥組成物之情形時，亦可於投予抗惡性腫瘤劑前投予本藥而使用。例如於化學療法中，亦可於抗惡性腫瘤劑之即將投予前~1小時30分鐘前投予本藥，第2天以後於上午投予而使用。 When the pharmaceutical composition of the present invention is used as a pharmaceutical composition for the prevention of nausea and vomiting caused by administration of an anti-neoplastic agent, the drug may be administered before administration of the anti-neoplastic agent. For example, in chemotherapy, the drug may be administered until 1 hour and 30 minutes before the immunization of the anti-neoplastic agent, and may be administered in the morning after the second day.

作為一實施樣態，本發明之式(I)所表示之化合物或其藥理學上容許之鹽亦可與除NK1受體拮抗劑以外之其他藥劑組合而使用。作為可組合而使用之其他藥劑，例如可列舉：皮質類固醇、及5-HT3受體拮抗型止吐劑。 As one embodiment, the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof can also be used in combination with other agents other than the NK 1 receptor antagonist. Examples of other agents that can be used in combination include a corticosteroid and a 5-HT 3 receptor antagonistic antiemetic.

於將本發明之式(I)所表示之化合物或其藥理學上容許之鹽與其他藥劑組合而使用之情形時，可以一併含有該等有效成分之製劑之形式投予，或者以將該等有效成分之各者分別製劑化而成之製劑之形式投予。於分別製劑化之情形時，可將該等製劑分別投予或同時投予。又，本發明之式(I)所表示之化合物或其藥理學上容許之鹽之投予亦可根據組合使用之其他藥劑之投予量而適當減量。 When the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof is used in combination with other agents, it may be administered in the form of a preparation containing the active ingredients together, or Each of the active ingredients is administered in the form of a preparation prepared separately. In the case of separate formulation, the preparations may be administered separately or simultaneously. Further, the administration of the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof may be appropriately reduced depending on the amount of the other agent to be used in combination.

[實施例] [Examples]

利用以下之參考例、實施例及試驗例進而詳細地說明本發明之內容，但本發明並不限定於此內容。 The contents of the present invention will be described in detail with reference to the following Reference Examples, Examples and Test Examples. However, the present invention is not limited thereto.

[參考例1] [Reference Example 1] (3-甲基哌啶-4-基)乙酸乙酯 (3-methylpiperidin-4-yl)ethyl acetate

於冰浴冷卻下於氫化鈉(含有率60%，0.17g)之四氫呋喃(5mL)懸浮液中添加膦醯基乙酸三乙酯(1.04g)，並於室溫下攪拌1小時。於室溫下於反應混合物中添加3-甲基-4-氧代哌啶-1-羧酸第三丁酯(0.50g) 之四氫呋喃(5mL)溶液，並於50℃下攪拌2.5小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得4-乙氧基羰基亞甲基-3-甲基哌啶-1-羧酸第三丁酯(0.65g)。於室溫下於所獲得之化合物(0.65g)之乙醇(12mL)溶液中添加10%鈀-碳(250mg，濕)，並於氫氣環境下在室溫下攪拌18小時。利用乙酸乙酯將反應混合物稀釋，並於室溫下攪拌15分鐘。對反應混合物進行矽藻土過濾，將濾液減壓濃縮，而獲得4-乙氧基羰基甲基-3-甲基哌啶-1-羧酸第三丁酯(0.64g)。於室溫下於所獲得之化合物(0.64g)之乙酸乙酯(10mL)溶液中添加4mol/L鹽酸(乙酸乙酯溶液，10mL)，並於室溫下攪拌39小時。將反應混合物減壓濃縮，於殘渣中添加飽和碳酸氫鈉水，並利用二氯甲烷-異丙醇(二氯甲烷：異丙醇=3：1)混合溶劑萃取2次。收集有機層，利用無水硫酸鈉進行乾燥，並於減壓下蒸餾去除，而獲得標題化合物(0.39g)。 Triethylphosphonium thioacetate (1.04 g) was added to a suspension of sodium hydride (yield: 60%, 0.17 g) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. Add 3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.50 g) to the reaction mixture at room temperature A solution of tetrahydrofuran (5 mL) was stirred at 50 ° C for 2.5 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate) to give 4-ethoxycarbonylmethylene-3-methylpiperidine-1-carboxylate. Tert-butyl acid ester (0.65 g). 10% palladium-carbon (250 mg, wet) was added to a solution of the obtained compound (0.65 g) in ethanol (12 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was diluted with ethyl acetate and stirred at room temperature for 15 min. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled of 3- ethoxycarbonylmethyl-3-methylpiperidine-1-carboxylate (0.64 g). 4 mol/L hydrochloric acid (ethyl acetate solution, 10 mL) was added to a solution of the obtained compound (0.64 g) in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 39 hr. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The organic layer was collected, dried over anhydrous sodium sulfate

[參考例2及3] [Reference Examples 2 and 3]

藉由與參考例1相同之方法，使用對應之原料而合成參考例2及3之化合物。 The compounds of Reference Examples 2 and 3 were synthesized by the same method as Reference Example 1 using the corresponding starting materials.

[參考例4] [Reference Example 4] (6-氯-4-碘吡啶-3-基)胺基甲酸第三丁酯 (6-chloro-4-iodopyridin-3-yl)carbamic acid tert-butyl ester

於氬氣環境下，於-78℃下向(6-氯吡啶-3-基)胺基甲酸第三丁酯(5.0g)及N,N,N',N'-四甲基乙烷-1,2-二胺(7.7g)之二***(120mL)溶液中滴 加正丁基鋰溶液(2.65mol/L正己烷溶液，25mL)。於-10℃下將該混合物攪拌2小時後，於-78℃下滴加碘(11.4g)之二***(40mL)溶液。於室溫下將該混合物攪拌一天。於反應混合物中添加飽和氯化銨水溶液，並利用二***進行萃取。將有機層利用10%焦亞硫酸鈉水溶液、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑；正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(2.59g)。 To (3-chloropyridin-3-yl)carbamic acid tert-butyl ester (5.0 g) and N,N,N',N'-tetramethylethane at -78 ° C under argon atmosphere 1,2-diamine (7.7g) in diethyl ether (120mL) solution A solution of n-butyllithium (2.65 mol/L n-hexane solution, 25 mL) was added. After the mixture was stirred at -10 °C for 2 hours, a solution of iodine (11.4 g) in diethyl ether (40 mL) was added dropwise at -78 °C. The mixture was stirred for one day at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The organic layer was washed with a 10% aqueous solution of sodium metabisulfite and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel chromatography eluting eluting

[參考例5] [Reference Example 5] (6-氯-4-碘吡啶-3-基)甲基胺基甲酸第三丁酯 (6-chloro-4-iodopyridin-3-yl)methylaminocarbamic acid tert-butyl ester

於冰浴冷卻下於(6-氯-4-碘吡啶-3-基)胺基甲酸第三丁酯(2.59g)之N,N-二甲基甲醯胺(30mL)溶液中添加氫化鈉(含有率60%，0.32g)，並於室溫下攪拌30分鐘。於冰浴冷卻下於該混合物中添加碘甲烷(2.60g)，並於室溫下攪拌整夜。於反應混合物中添加飽和碳酸氫鈉水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基化矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(2.66g)。 Add sodium hydride to a solution of (6-chloro-4-iodopyridin-3-yl)carbamic acid tert-butyl ester (2.59 g) in N,N-dimethylformamide (30 mL) (content ratio 60%, 0.32 g), and stirred at room temperature for 30 minutes. Methyl iodide (2.60 g) was added to the mixture under ice-cooling and stirred at room temperature overnight. Saturated sodium hydrogencarbonate water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc)

[參考例6] [Reference Example 6] (6-氯-4-碘吡啶-3-基)甲基胺 (6-chloro-4-iodopyridin-3-yl)methylamine

於冰浴冷卻下於(6-氯-4-碘吡啶-3-基)甲基胺基甲酸第三丁酯(2.66g)之二氯甲烷(10mL)溶液中添加三氟乙酸(8.23g)，並於室溫下攪拌2小時。將反應混合物於減壓下濃縮，於殘渣中添加飽和碳酸鈉水溶液， 利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下濃縮，而獲得標題化合物(1.89g)。 Trifluoroacetic acid (8.23 g) was added to a solution of (6-chloro-4-iodopyridin-3-yl)methylcarbamic acid tert-butyl ester (2.66 g) in dichloromethane (10 mL) And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium Extraction was carried out using ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate.

[參考例7] [Reference Example 7] [6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]甲基胺 [6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]methylamine

於室溫下於(6-氯-4-碘吡啶-3-基)甲基胺(1.89g)及4-氟-2-甲基苯基硼酸(1.30g)之1,2-二甲氧基乙烷(20mL)-水(20mL)混合溶液中添加乙酸鈀(II)(0.16g)、三苯基膦(0.37g)及碳酸鈉(3.73g)，並於90℃下攪拌整夜。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基化矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(1.56g)。 1,2-Dimethoxygen at (6-chloro-4-iodopyridin-3-yl)methylamine (1.89 g) and 4-fluoro-2-methylphenylboronic acid (1.30 g) at room temperature Palladium(II) acetate (0.16 g), triphenylphosphine (0.37 g) and sodium carbonate (3.73 g) were added to a mixed solution of ethyl ethane (20 mL) and water (20 mL), and stirred at 90 ° C overnight. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc)

[參考例8] [Reference Example 8] (6-氯-4-鄰甲苯基吡啶-3-基)甲基胺 (6-chloro-4-o-tolypyridin-3-yl)methylamine

於室溫下於(6-氯-4-碘吡啶-3-基)甲基胺(0.70g)及2-甲基苯基硼酸(0.42g)之1,2-二甲氧基乙烷(10mL)-水(10mL)混合溶液中添加乙酸鈀(II)(0.058g)、三苯基膦(0.14g)及碳酸鈉(1.38g)，並於90℃下攪拌整夜。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(0.54g)。 1,2-Dimethoxyethane (6-chloro-4-iodopyridin-3-yl)methylamine (0.70 g) and 2-methylphenylboronic acid (0.42 g) at room temperature ( Palladium(II) acetate (0.058 g), triphenylphosphine (0.14 g) and sodium carbonate (1.38 g) were added to a mixed solution of 10 mL)-water (10 mL), and stirred at 90 ° C overnight. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel chromatography eluting eluting

[參考例9] [Reference Example 9] 2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺 2-(3,5-bistrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N-methylisobutyl Base amine

於室溫下於2-(3,5-雙三氟甲基苯基)-2-甲基丙酸(0.66g)之二氯甲烷溶液(10mL)中添加草醯氯(0.56g)及N,N-二甲基甲醯胺(2滴)，並於該溫度下攪拌1小時。將反應混合物於減壓下濃縮，而獲得殘渣。於氬氣環境下，於冰浴冷卻下向[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]甲基胺(0.50g)之四氫呋喃(10mL)溶液中添加雙(三甲基矽烷基)醯胺鉀(0.500mol/L甲苯溶液，5.0mL)，並於室溫下攪拌30分鐘。於冰浴冷卻下於反應混合物中滴加上述殘渣之四氫呋喃(5mL)溶液，並於室溫下攪拌2小時。於反應混合物中添加1.0mol/L碳酸氫鈉水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基化矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(1.03g)。 Add oxalic acid chloride (0.56 g) and N to a solution of 2-(3,5-bistrifluoromethylphenyl)-2-methylpropanoic acid (0.66 g) in dichloromethane (10 mL). N-dimethylformamide (2 drops) and stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. To a solution of [6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]methylamine (0.50 g) in tetrahydrofuran (10 mL) under argon. Bis(trimethyldecyl) decylamine potassium (0.500 mol/L in toluene solution, 5.0 mL) was added thereto, and stirred at room temperature for 30 minutes. A solution of the above residue in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. 1.0 mol/L of sodium hydrogencarbonate water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc EtOAcjjjjj

[參考例10] [Reference Example 10] 2-(3,5-雙三氟甲基苯基)-N-(6-氯-4-鄰甲苯基吡啶-3-基)-N-甲基異丁基醯胺 2-(3,5-bistrifluoromethylphenyl)-N-(6-chloro-4-o-tolypyridin-3-yl)-N-methylisobutylguanamine

於室溫下於2-(3,5-雙三氟甲基苯基)-2-甲基丙酸(0.77g)之二氯甲烷溶液(12mL)中添加草醯氯(0.65g)及N,N-二甲基甲醯胺(2滴)，並於該溫度下攪拌1小時。將反應混合物於減壓下濃縮，而獲得殘渣。於氬氣環境下，於冰浴冷卻下向(6-氯-4-鄰甲苯基吡啶-3-基)甲基胺(0.54g)之四氫呋喃(12mL)溶液中添加雙(三甲基矽烷基)醯胺鉀(0.500mol/L甲苯溶液，6.0mL)，並於室溫下攪拌30分鐘。於冰浴冷卻下，於反應 混合物中滴加上述殘渣之四氫呋喃(6mL)溶液，並於室溫下攪拌1小時。於反應混合物中添加1.0mol/L碳酸氫鈉水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基化矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯)對所獲得之粗產物進行純化，而獲得標題化合物(1.0g)。 Add oxalic acid chloride (0.65 g) and N to a solution of 2-(3,5-bistrifluoromethylphenyl)-2-methylpropanoic acid (0.77 g) in dichloromethane (12 mL). N-dimethylformamide (2 drops) and stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Add bis(trimethyldecyl) to a solution of (6-chloro-4-o-tolypyridin-3-yl)methylamine (0.54 g) in tetrahydrofuran (12 mL) under argon. Potassium guanamine (0.500 mol/L in toluene, 6.0 mL) and stirred at room temperature for 30 minutes. In the ice bath cooling, in the reaction A solution of the above residue in tetrahydrofuran (6 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. 1.0 mol/L of sodium hydrogencarbonate water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc)

[參考例11] [Reference Example 11] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl -3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.79g)、哌啶-4-基乙酸乙酯(0.38g)及碳酸鉀(0.41g)之二甲基亞碸(4.5mL)懸浮液於180℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=100/0~60/40)對所獲得之粗產物進行純化。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=100/0~60/40)對所獲得之純化物進行純化，而獲得標題化合物(0.38g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation a suspension of methyl isobutyl decylamine (0.79 g), ethyl piperidin-4-ylacetate (0.38 g) and potassium carbonate (0.41 g) in dimethyl hydrazine (4.5 mL) stirred at 180 ° C 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by aminopropyl hydrazine gel column chromatography (solvent solvent: n-hexane/ethyl acetate = 100/0 to 60/40). The obtained purified product was purified by silica gel column chromatography (yield: hexane/ethyl acetate = 100/0 to 60/40) to give the title compound (0.38 g).

[參考例12] [Reference Example 12] (5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-鄰甲苯基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基)乙酸乙酯 (5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-o-tolyl-3,4,5,6 -tetrahydro-2H-[1,2']bipyridin-4-yl)ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-(6-氯-4-鄰甲苯基吡啶 -3-基)-N-甲基異丁基醯胺(0.50g)、哌啶-4-基乙酸乙酯(0.25g)及碳酸鉀(0.27g)之二甲基亞碸(3.0mL)懸浮液於180℃下攪拌2小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.35g)。 2-(3,5-bistrifluoromethylphenyl)-N-(6-chloro-4-o-tolylpyridine under microwave irradiation -3-yl)-N-methylisobutylguanamine (0.50 g), ethyl piperidin-4-ylacetate (0.25 g) and potassium carbonate (0.27 g) in dimethyl hydrazine (3.0 mL) The suspension was stirred at 180 ° C for 2 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography eluting eluting

[參考例13] [Reference Example 13] 5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,3-二甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl) -3,3-Dimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.05g)及(3,3-二甲基哌啶-4-基)乙酸乙酯(0.094g)之1-甲基-2-吡咯啶酮(0.5mL)溶液於180℃下攪拌3小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.043g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation Methyl isobutyl decylamine (0.05 g) and (3,3-dimethylpiperidin-4-yl)acetate (0.094 g) of 1-methyl-2-pyrrolidone (0.5 mL) The solution was stirred at 180 ° C for 3 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAcjjjjjjjjjj

[參考例14] [Reference Example 14] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.05g)及(3-甲基哌啶-4-基)乙酸乙酯(0.087g)之1-甲基-2-吡咯啶酮(0.5mL)溶液於180℃下攪拌1小時。 將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.040g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation a solution of methyl isobutyl decylamine (0.05 g) and (3-methylpiperidin-4-yl)acetate (0.087 g) in 1-methyl-2-pyrrolidone (0.5 mL) at 180 Stir at ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography eluting eluting

[參考例15] [Reference Example 15] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲氧基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3-methoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.05g)及(3-甲氧基哌啶-4-基)乙酸乙酯(0.094g)之1-甲基-2-吡咯啶酮(0.5mL)溶液於180℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~60/40)對所獲得之粗產物進行純化，而獲得標題化合物(0.025g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation a solution of methyl isobutyl decylamine (0.05 g) and (3-methoxypiperidin-4-yl)acetate (0.094 g) in 1-methyl-2-pyrrolidone (0.5 mL) Stir at 180 ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc

[參考例16] [Reference Example 16] 2-甲基-2-哌啶-4-基丙酸乙酯 Ethyl 2-methyl-2-piperidin-4-ylpropanoate

於氬氣環境下，於-78℃下向二異丙基醯胺鋰(1.09mol/L四氫呋喃-正己烷溶液，30.0mL)之四氫呋喃(40mL)溶液中滴加異丁酸乙酯(3.48g)之四氫呋喃(20mL)溶液，並於該溫度下攪拌1小時。於-78℃下於反應混合物中添加4-氧代哌啶-1-羧酸苄酯(5.83g)之四氫呋喃(50mL)溶液，並於室溫下攪拌整夜。於反應混合物中添加飽和氯化銨水溶液，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無 水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=90/10~10/90)對所獲得之粗產物進行純化，而獲得4-(1-乙氧基羰基-1-甲基乙基)-4-羥基脈啶-1-羧酸苄酯(6.13g)。於室溫下於所獲得之化合物(6.13g)之甲苯(100mL)溶液中添加氫氧化(甲氧基羰基胺磺醯基)三乙基銨分子內鹽(5.00g)，並於90℃下攪拌2小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用飽和碳酸氫鈉水、水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得4-(1-乙氧基羰基-1-甲基乙基)-3,6-二氫-2H-吡啶-1-羧酸苄酯(5.85g)。於氫氣環境下，將所獲得之化合物(5.85g)與Pearlman觸媒(0.600g)之甲醇(65mL)-乙酸乙酯(65mL)混合物於室溫下攪拌整夜。對反應混合物進行矽藻土過濾，將濾液於減壓下濃縮而獲得標題化合物(3.18g)。 Ethyl isobutyrate (3.48 g) was added dropwise to a solution of lithium diisopropylamide (1.09 mol/L tetrahydrofuran-n-hexane solution, 30.0 mL) in tetrahydrofuran (40 mL) at -78 °C. A solution of tetrahydrofuran (20 mL) was stirred at this temperature for 1 hour. A solution of benzyl 4-oxopiperidine-l-carboxylate (5.83 g) in tetrahydrofuran (50 mL) was added to the mixture and then stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. After washing the organic layer with water and saturated brine, use no The water magnesium sulfate was dried and distilled off under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate = 90/10 to 10/90) to obtain 4-(1-ethoxycarbonyl-1- Methyl ethyl)-4-hydroxycyclidine-1-carboxylic acid benzyl ester (6.13 g). Adding (methoxycarbonylaminesulfonyl)triethylammonium intramolecular salt (5.00 g) to a solution of the obtained compound (6.13 g) in toluene (100 mL) at room temperature and at 90 ° C Stir for 2 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate = 100/0 to 50/50) to obtain 4-(1-ethoxycarbonyl-1- Methyl ethyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5.85 g). A mixture of the obtained compound (5.85 g) and EtOAc (EtOAc) (EtOAc) The reaction mixture was subjected to EtOAc.

[參考例17] [Reference Example 17] 2-哌啶-4-基丙酸乙酯 Ethyl 2-piperidin-4-ylpropanoate

於冰浴冷卻下於氫化鈉(含有率60%，0.78g)之N,N-二甲基甲醯胺(20mL)懸浮液中添加2-(二乙氧基磷醯基)丙酸乙酯(4.44g)，並於該溫度下攪拌30分鐘。於冰浴冷卻下於反應混合物中添加4-氧代哌啶-1-羧酸苄酯(3.50g)之N,N-二甲基甲醯胺(10mL)溶液，並於室溫下攪拌1小時。於反應混合物中添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得4-(1-乙氧基羰基亞乙基)哌啶-1- 羧酸苄酯(4.60g)。於氫氣環境下，將所獲得之化合物(4.60g)與10%鈀-碳(500mg，濕)之甲醇(50mL)混合物於室溫下攪拌2小時。對反應混合物進行矽藻土過濾，將濾液減壓濃縮而獲得標題化合物(2.85g)。 Add ethyl 2-(diethoxyphosphonium)propionate to a suspension of sodium hydride (60%, 0.78 g) in N,N-dimethylformamide (20 mL) with ice-cooling. (4.44 g) and stirred at this temperature for 30 minutes. A solution of benzyl 4-oxopiperidine-1-carboxylate (3.50 g) in N,N-dimethylformamide (10 mL) was added to the reaction mixture and the mixture was stirred at room temperature. hour. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate = 100/0 to 50/50) to obtain 4-(1-ethoxycarbonylethylidene). Piperidine-1- Benzyl carboxylate (4.60 g). A mixture of the obtained compound (4.60 g) and 10% palladium-carbon (500 mg, wet) in methanol (50 mL) was stirred at room temperature for 2 hr. The reaction mixture was subjected to EtOAc (EtOAc)EtOAc.

[參考例18] [Reference Example 18] (4-甲基哌啶-4-基)乙酸乙酯 (4-methylpiperidin-4-yl)ethyl acetate

於室溫下於4-羥基甲基-4-甲基哌啶-1-羧酸第三丁酯(0.67g)與三乙胺(0.44g)之二氯甲烷(15mL)溶液中添加甲磺醯氯(0.40g)，並於該溫度下攪拌3小時。將反應混合物利用水、飽和鹽水清洗，並利用無水硫酸鎂進行乾燥。將溶劑於減壓下蒸餾去除而獲得4-甲磺醯氧基甲基-4-甲基哌啶-1-羧酸第三丁酯(0.85g)。於室溫下於所獲得之化合物(0.85g)之N,N-二甲基甲醯胺(6mL)溶液中添加氰化鈉(0.27g)，並於50℃下攪拌5小時，於80℃下攪拌13小時。於反應混合物中添加氰化鈉(0.22g)及碘化鈉(0.02g)，並於120℃下攪拌8小時。於反應混合物中添加氰化鉀(0.72g)，並於140℃下攪拌17小時。將反應混合物冷卻至室溫後，添加水，並利用正己烷-乙酸乙酯(1/4)混合液進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=80/20~50/50)對所獲得之粗產物進行純化，而獲得4-氰基甲基-4-甲基哌啶-1-羧酸第三丁酯(0.53g)。將所獲得之化合物(0.53g)與濃鹽酸(12mL)之混合物於110℃下攪拌47小時。將反應混合物冷卻至室溫後，添加水(24mL)、氫氧化鈉水溶液(2.0mol/L，45mL)及二碳酸二第三丁酯(0.51g)，並於室溫下攪拌21小時。將溶劑於減壓下濃縮，於殘渣中添加水、鹽酸(2.0mol/L，3mL)，利用乙酸乙酯進行萃取。利用無水硫酸鈉使有機層乾 燥，於減壓下蒸餾去除而獲得4-羧甲基-4-甲基哌啶-1-羧酸第三丁酯(0.34g)。於室溫下於所獲得之化合物(0.34g)之N,N-二甲基甲醯胺(5mL)溶液中添加碳酸鉀(0.27g)及碘乙烷(0.41g)，並於該溫度下攪拌22小時。於反應混合物中添加水，並利用二***進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷-乙酸乙酯=100/0~60/40)對所獲得之粗產物進行純化，而獲得4-乙氧基羰基甲基-4-甲基哌啶-1-羧酸第三丁酯(0.28g)。於室溫下於所獲得之化合物(0.28g)之1,4-二烷(5mL)溶液中添加氯化氫(4.0mol/L之1,4-二烷溶液，5.0mL)，並於該溫度下攪拌26小時。將溶劑於減壓下濃縮，於殘渣中添加飽和碳酸氫鈉水，並利用二氯甲烷-異丙醇(3/1)混合液萃取2次。利用無水硫酸鈉使所合併之有機層乾燥，於減壓下蒸餾去除而獲得標題化合物(0.17g)。 Adding methyl sulfonate to a solution of 3-hydroxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.67 g) and triethylamine (0.44 g) in dichloromethane (15 mL) Chlorochloride (0.40 g) was added and stirred at this temperature for 3 hours. The reaction mixture was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-methanesulfonyloxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.85 g). Add sodium cyanide (0.27 g) to a solution of the obtained compound (0.85 g) in N,N-dimethylformamide (6 mL) at room temperature and stir at 50 ° C for 5 hours at 80 ° C Stir under 13 hours. Sodium cyanide (0.22 g) and sodium iodide (0.02 g) were added to the reaction mixture, and stirred at 120 ° C for 8 hours. Potassium cyanide (0.72 g) was added to the reaction mixture, and stirred at 140 ° C for 17 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with a mixture of n-hexane-ethyl acetate (1/4). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate = 80/20 to 50/50) to obtain 4-cyanomethyl-4-methylper. Butane-1-carboxylic acid tert-butyl ester (0.53 g). A mixture of the obtained compound (0.53 g) and concentrated hydrochloric acid (12 mL) was stirred at 110 ° C for 47 hr. After cooling the reaction mixture to room temperature, water (24 mL), aqueous sodium hydroxide (2.0 mol/L, 45 mL) and dibutyl succinate (0.51 g) were added, and the mixture was stirred at room temperature for 21 hours. The solvent was concentrated under reduced pressure, and water and hydrochloric acid (2.0 mol/L, 3 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness toield toield of 4-carboxymethyl-4-methylpiperidine-1-carboxylic acid (0.34 g). Potassium carbonate (0.27 g) and ethyl iodide (0.41 g) were added to a solution of the obtained compound (0.34 g) in N,N-dimethylformamide (5 mL) at room temperature and at this temperature Stir for 22 hours. Water was added to the reaction mixture, and extraction was carried out with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane-ethyl acetate = 100/0 to 60/40) to obtain 4-ethoxycarbonylmethyl-4-methyl. Third piperazine (0.28 g). 1,4-two of the obtained compound (0.28 g) at room temperature Add hydrogen chloride (4.0mol/L of 1,4-two) to the alkane (5mL) solution Alkane solution, 5.0 mL), and stirred at this temperature for 26 hours. The solvent was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted twice with a mixture of dichloromethane and isopropyl alcohol (3/1). The combined organic layer was dried over anhydrous sodium

[參考例19] [Reference Example 19] 6-氯-3-硝基吡啶-2-甲腈 6-chloro-3-nitropyridine-2-carbonitrile

於室溫下於2,6-二氯-3-硝基吡啶(2.50g)之N-甲基吡咯啶酮(25mL)溶液中添加氰化銅(I)(2.32g)，並於180℃下攪拌1小時。將反應混合物冷卻至室溫後，添加乙酸乙酯及水，對混合物進行矽藻土過濾。將濾液利用飽和鹽水清洗，利用乙酸乙酯再萃取水層。將所合併之有機層利用水、飽和鹽水清洗，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~70/30)對所獲得之粗產物進行純化，而獲得標題化合物(0.90g)。 Add copper (I) cyanide (2.32 g) to a solution of 2,6-dichloro-3-nitropyridine (2.50 g) in N-methylpyrrolidone (25 mL) at rt. Stir under 1 hour. After cooling the reaction mixture to room temperature, ethyl acetate and water were added, and the mixture was filtered over Celite. The filtrate was washed with saturated brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography eluting eluting

[參考例20] [Reference Example 20] 3-胺基-6-氯吡啶-2-甲腈 3-amino-6-chloropyridine-2-carbonitrile

於室溫下於6-氯-3-硝基吡啶-2-甲腈(0.32g)及濃鹽酸(1.2mL)之乙醇(3.6mL)溶液中添加鐵粉(0.34g)，並加熱回流30分鐘。將反應混合物冷卻至室溫後，添加飽和碳酸氫鈉水而設為鹼性。添加乙酸乙酯後，對混合物進行矽藻土過濾，並利用乙酸乙酯萃取濾液。將有機層利用水、飽和鹽水清洗，利用無水硫酸鎂進行乾燥。將溶劑於減壓下濃縮，而獲得標題化合物(0.24g)。 Iron powder (0.34 g) was added to a solution of 6-chloro-3-nitropyridine-2-carbonitrile (0.32 g) and concentrated hydrochloric acid (1.2 mL) in ethanol (3.6 mL) at room temperature and heated to reflux 30 minute. After cooling the reaction mixture to room temperature, saturated sodium hydrogencarbonate water was added to make it alkaline. After ethyl acetate was added, the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give crystall

[參考例21] [Reference Example 21] 3-胺基-4-溴-6-氯吡啶-2-甲腈 3-amino-4-bromo-6-chloropyridine-2-carbonitrile

於室溫下於3-胺基-6-氯吡啶-2-甲腈(0.24g)之N,N-二甲基甲醯胺(8mL)溶液中添加N-溴丁二醯亞胺(0.37g)，並於該溫度下攪拌整夜。於反應混合物中添加飽和硫代硫酸鈉水溶液，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=75/25~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.30g)。 Add N-bromobutaneimine (0.37) to a solution of 3-amino-6-chloropyridine-2-carbonitrile (0.24 g) in N,N-dimethylformamide (8 mL) at rt. g) and stir at this temperature overnight. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) .

[參考例22] [Reference Example 22] 3-胺基-6-氯-4-(4-氟-2-甲基苯基)吡啶-2-甲腈 3-amino-6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-2-carbonitrile

於微波照射下將3-胺基-4-溴-6-氯吡啶-2-甲腈(0.15g)、4-氟-2-甲基苯基硼酸(0.08g)、四(三苯基膦)鈀(0)(0.07g)、碳酸鈉(0.20g)、1,2-二甲氧基乙烷(3.2mL)及水(0.8mL)之混合物於100℃下攪拌1小時。 將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用飽和碳酸氫鈉水、飽和鹽水清洗，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由膠基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=50/50~0/100)對所獲得之粗產物進行純化，而獲得標題化合物(0.14g)。 3-Amino-4-bromo-6-chloropyridine-2-carbonitrile (0.15 g), 4-fluoro-2-methylphenylboronic acid (0.08 g), tetrakis(triphenylphosphine) under microwave irradiation A mixture of palladium (0) (0.07 g), sodium carbonate (0.20 g), 1,2-dimethoxyethane (3.2 mL) and water (0.8 mL) was stirred at 100 ° C for one hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The obtained crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc .

[參考例23] [Reference Example 23] 2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3-基]異丁基醯胺 2-(3,5-bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]isobutyl Base amine

於室溫下於2-(3,5-雙三氟甲基苯基)-2-甲基丙酸(0.31g)之二氯甲烷溶液(2.6mL)中添加草醯氯(0.26g)及N,N-二甲基甲醯胺(2滴)，並於該溫度下攪拌1小時。將反應混合物於減壓下濃縮，而獲得殘渣。於冰浴冷卻下於3-胺基-6-氯-4-(4-氟-2-甲基苯基)吡啶-2-甲腈(0.14g)之四氫呋喃(5mL)溶液中滴加雙(三甲基矽烷基)醯胺鈉溶液(1.0mol/L四氫呋喃溶液，1.1mL)，並於該溫度下攪拌30分鐘。於冰浴冷卻下於反應混合物中滴加上述殘渣之四氫呋喃(2.0mL)溶液，並於室溫下攪拌30分鐘。於反應混合物中添加飽和碳酸氫鈉水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=85/15~40/60)對所獲得之粗產物進行純化，而獲得標題化合物(0.21g)。 Add oxalic acid chloride (0.26 g) to a solution of 2-(3,5-bistrifluoromethylphenyl)-2-methylpropanoic acid (0.31 g) in dichloromethane (2.6 mL) N,N-dimethylformamide (2 drops) and stirred at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Add a double solution in a solution of 3-amino-6-chloro-4-(4-fluoro-2-methylphenyl)pyridine-2-carbonitrile (0.14 g) in tetrahydrofuran (5 mL) Trimethylsulfonyl) sodium decylamine solution (1.0 mol/L tetrahydrofuran solution, 1.1 mL) was stirred at this temperature for 30 minutes. A solution of the above residue in tetrahydrofuran (2.0 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. Saturated sodium hydrogencarbonate water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc (EtOAc: EtOAc (EtOAc) .

[參考例24] [Reference Example 24] 2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3- 基]-N-甲基異丁基醯胺 2-(3,5-bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridine-3- -N-methylisobutyl decylamine

於冰浴冷卻下於2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3-基]異丁基醯胺(0.21g)之N,N-二甲基甲醯胺(2.4mL)溶液中添加氫化鈉(含有率60%，0.018g)，並於該溫度下攪拌5分鐘。於冰浴冷卻下於反應混合物中添加碘甲烷(0.11g)，並於室溫下攪拌整夜。於反應混合物中添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.09g)。 Ethyl 2-(3,5-bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridine- Add sodium hydride (content 60%, 0.018 g) to a solution of 3-methyl]isobutylguanamine (0.21 g) in N,N-dimethylformamide (2.4 mL), and stir at this temperature 5 minute. Methyl iodide (0.11 g) was added to the reaction mixture under ice-cooling, and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexanes: hexanes:

[參考例25] [Reference Example 25] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4-fluoro- 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.03g)、哌啶-4-基乙酸乙酯(0.05g)及碳酸鉀(0.02g)之二甲基亞碸(1.0mL)懸浮液於100℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=80/20~20/80)對所獲得之粗產物進行純化，而獲得標題化合物(0.02g)。 2-(3,5-Bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridine-3 under microwave irradiation a suspension of -N-methylisobutylguanamine (0.03 g), ethyl piperidin-4-ylacetate (0.05 g) and potassium carbonate (0.02 g) in dimethylidene (1.0 mL) Stir at 100 ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc .

[參考例26] [Reference Example 26] 2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲 基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]-2-甲基丙酸乙酯 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methyl Ethylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]-2-methylpropanoate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.15g)、2-甲基-2-哌啶-4-基丙酸乙酯(0.28g)及N-甲基吡咯啶酮(1.5mL)之混合物於190℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=100/0~60/40)對所獲得之粗產物進行純化，而獲得標題化合物(0.14g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation a mixture of methyl isobutyl decylamine (0.15 g), ethyl 2-methyl-2-piperidin-4-ylpropanoate (0.28 g) and N-methylpyrrolidone (1.5 mL) at 190 Stir at ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (yield: hexane/ethyl acetate=100/0~60/40) to give the title compound (0.14 g).

[參考例27] [Reference Example 27] 2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸乙酯 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methyl Phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid ethyl ester

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.48g)、2-哌啶-4-基丙酸乙酯(0.83g)及碳酸鉀(0.25g)之N-甲基吡咯啶酮(3.6mL)懸浮液於190℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化，而獲得標題化合物(0.51g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation a suspension of methyl isobutyl decylamine (0.48 g), ethyl 2-piperidin-4-ylpropionate (0.83 g) and potassium carbonate (0.25 g) in N-methylpyrrolidone (3.6 mL) Stir at 190 ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (yield: hexane/ethyl acetate=100/0 to 50/50) to give the title compound (0.51 g).

[參考例28及參考例29] [Reference Example 28 and Reference Example 29] N-[4-[(S)-2-((S)-4-苄基-2-氧代唑啶-3-基)-1-甲基-2-氧代乙基]-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基]-2-(3,5-雙三氟甲基苯基)-N-甲基異丁基醯胺(參考例28)、及N-[4-[(R)-2-((S)-4-苄基-2-氧 代唑啶-3-基)-1-甲基-2-氧代乙基]-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基]-2-(3,5-雙三氟甲基苯基)-N-甲基異丁基醯胺(參考例29) N-[4-[(S)-2-((S)-4-benzyl-2-oxo) Zoxadin-3-yl)-1-methyl-2-oxoethyl]-4'-(4-fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H- [1,2']bipyridyl-5'-yl]-2-(3,5-bistrifluoromethylphenyl)-N-methylisobutylguanamine (Reference Example 28), and N-[ 4-[(R)-2-((S)-4-benzyl-2-oxo) Zoxadin-3-yl)-1-methyl-2-oxoethyl]-4'-(4-fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H- [1,2']bipyridyl-5'-yl]-2-(3,5-bistrifluoromethylphenyl)-N-methylisobutylguanamine (Reference Example 29)

於微波照射下將2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸乙酯(0.50g)、氫氧化鈉水溶液(1.0mol/L，2.0mL)、四氫呋喃(2mL)及甲醇(6mL)之混合物於140℃下攪拌2小時。將反應混合物冷卻至室溫後，添加鹽酸(1.0mol/L，3.0mL)，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=50/50~0/100)對所獲得之粗產物進行純化，而獲得2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸(0.42g)。於氬氣環境下，於-78℃下向(S)-4-苄基唑啶-2-酮(0.06g)之四氫呋喃(4mL)溶液中滴加正丁基鋰(2.65mol/L正己烷溶液，0.12mL)，並於該溫度下攪拌30分鐘，而獲得(S)-4-苄基唑啶-2-酮之鋰溶液。於氬氣環境下，於冰浴冷卻下向2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸(0.20g)及三乙胺(0.04g)之二***(4mL)溶液中添加三甲基乙醯氯(0.04g)，並於該溫度下攪拌1小時。於-78℃下於反應混合物中滴加上述鋰溶液，並於冰浴冷卻下攪拌1小時。於反應混合物中添加飽和氯化銨水溶液，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~10/90)對所獲得之粗產物進行純化。藉由矽膠管 柱層析法(溶出溶劑：正己烷/乙酸乙酯=100/0~50/50)對所獲得之粗產物進行純化。藉由製備薄層層析法(矽膠厚0.5mm，溶出溶劑：正己烷/乙酸乙酯=2/1)對所獲得之粗產物進行純化，而獲得參考例28之化合物(0.09g)及參考例29之化合物(0.09g)。於上述層析法中，高極性側之化合物為參考例28之化合物，低極性側之化合物為參考例29之化合物。 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropenyl]methylamino}-4'-(4-fluoro) under microwave irradiation 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid ethyl ester (0.50 g), aqueous sodium hydroxide solution (1.0 A mixture of mol/L, 2.0 mL), tetrahydrofuran (2 mL) and methanol (6 mL) was stirred at 140 ° C for 2 hr. After cooling the reaction mixture to room temperature, hydrochloric acid (1.0 mol/L, 3.0 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by a silica gel column chromatography (solvent solvent: n-hexane/ethyl acetate = 50/50 to 0/100) to obtain 2-[5'-{[2-(3) ,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl)-3,4,5,6- Tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid (0.42 g). (S)-4-benzyl group at -78 ° C under argon n-Butyllithium (2.65 mol/L n-hexane solution, 0.12 mL) was added dropwise to a solution of oxazolidine-2-one (0.06 g) in tetrahydrofuran (4 mL), and stirred at this temperature for 30 minutes to obtain (S) -4-benzyl A lithium solution of oxazolidine-2-one. Under an argon atmosphere, under ice cooling to 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}- 4'-(4-Fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid (0.20 g) and three To a solution of diethylamine (0.04 g) in diethyl ether (4 mL) was added trimethylethylamine (0.04 g), The above lithium solution was added dropwise to the reaction mixture at -78 ° C, and stirred for 1 hour under ice-cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent solvent: n-hexane/ethyl acetate = 90/10 to 10/90). The obtained crude product was purified by silica gel column chromatography (solvent solvent: n-hexane/ethyl acetate = 100/0 to 50/50). The obtained crude product was purified by preparative thin-layer chromatography (yield: 0.5 mm thick, solvent: n-hexane/ethyl acetate = 2/1) to obtain the compound of Reference Example 28 (0.09 g) and the reference Compound of Example 29 (0.09 g). In the above chromatography, the compound on the highly polar side was the compound of Reference Example 28, and the compound on the low polarity side was the compound of Reference Example 29.

[參考例30] [Reference Example 30] 2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸乙酯 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4- Ethyl fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.06g)、2-哌啶-4-基丙酸乙酯(0.10g)及碳酸鉀(0.03g)之二甲基亞碸(1.0mL)懸浮液於180℃下攪拌2小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~65/35)對所獲得之粗產物進行純化，而獲得標題化合物(0.05g)。 2-(3,5-Bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridine-3 under microwave irradiation -N-methylisobutylguanamine (0.06 g), 2-piperidin-4-ylpropionic acid ethyl ester (0.10 g) and potassium carbonate (0.03 g) in dimethyl hydrazine (1.0 mL) The suspension was stirred at 180 ° C for 2 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc (EtOAc: EtOAc (EtOAc) .

[參考例31] [Reference Example 31] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]ethyl acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.05g)、(4-甲基哌啶-4-基)乙酸乙 酯(0.09g)及N-甲基吡咯啶酮(0.5mL)之混合物於190℃下攪拌30分鐘。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~60/40)對所獲得之粗產物進行純化，而獲得標題化合物(0.03g)。 2-(3,5-Bislicotrifluoromethylphenyl)-N-[6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl]-N under microwave irradiation -methylisobutylguanamine (0.05g), (4-methylpiperidin-4-yl)acetate B A mixture of the ester (0.09 g) and N-methylpyrrolidone (0.5 mL) was stirred at 190 ° C for 30 min. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:

[參考例32] [Reference Example 32] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4-fluoro- Ethyl 2-methylphenyl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate

於微波照射下將2-(3,5-雙三氟甲基苯基)-N-[6-氯-2-氰基-4-(4-氟-2-甲基苯基)吡啶-3-基]-N-甲基異丁基醯胺(0.06g)、(4-甲基哌啶-4-基)乙酸乙酯(0.09g)及碳酸鉀(0.03g)之二甲基亞碸(1.0mL)懸浮液於180℃下攪拌1小時。將反應混合物冷卻至室溫後，添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除。藉由胺基丙基矽烷化矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~65/35)對所獲得之粗產物進行純化，而獲得標題化合物(0.06g)。 2-(3,5-Bistrifluoromethylphenyl)-N-[6-chloro-2-cyano-4-(4-fluoro-2-methylphenyl)pyridine-3 under microwave irradiation -N-methylisobutylguanamine (0.06g), (4-methylpiperidin-4-yl)acetate (0.09g) and potassium carbonate (0.03g) of dimethyl hydrazine (1.0 mL) The suspension was stirred at 180 ° C for 1 hour. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) .

[實施例1] [Example 1] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.38g)之四氫呋喃(6mL)-甲醇(6mL)-水(2mL)混合液中添加氫氧化鋰 一水合物(0.12g)，並於室溫下攪拌整夜。於反應混合物中添加2mol/L鹽酸(1.5mL)進行中和，將該混合物於減壓下濃縮。於殘渣中添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.37g)。 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2) at room temperature -Methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.38 g) in tetrahydrofuran (6 mL)-methanol (6 mL) - Add lithium hydroxide to the water (2mL) mixture The monohydrate (0.12 g) was stirred at room temperature overnight. 2 mol/L hydrochloric acid (1.5 mL) was added to the reaction mixture for neutralization, and the mixture was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate.

[實施例2] [Embodiment 2] (5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-鄰甲苯基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基)乙酸 (5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-o-tolyl-3,4,5,6 -tetrahydro-2H-[1,2']bipyridin-4-yl)acetic acid

於室溫下於(5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-鄰甲苯基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基)乙酸乙酯(0.30g)之四氫呋喃(4mL)-甲醇(2mL)-水(2mL)混合液中添加氫氧化鋰一水合物(0.084g)，並於室溫下攪拌3小時。於反應混合物中添加2mol/L鹽酸(1.1mL)進行中和，將該混合物於減壓下濃縮。於殘渣中添加水，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.29g)。 (5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-o-tolyl-3, at room temperature, Addition of 4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl)acetate (0.30 g) in tetrahydrofuran (4 mL)-methanol (2 mL)-water (2 mL) Lithium hydroxide monohydrate (0.084 g) was stirred at room temperature for 3 hours. 2 mol/L hydrochloric acid (1.1 mL) was added to the reaction mixture for neutralization, and the mixture was concentrated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate.

[實施例3] [Example 3] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,3-二甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3,3-dimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,3-二甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.043g)之四氫呋喃(1mL)-乙醇(0.5mL)-水(0.5mL)混合液中添加氫氧化鋰一水合物(0.012g)，並於室溫下攪拌3小時。於反應混合物中添加2mol/L鹽酸(0.14mL)進行中和，於該混合物中添加水，利 用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.033g)。 5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-) at room temperature Methylphenyl)-3,3-dimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.043 g) in tetrahydrofuran ( To a mixed liquid of 1 mL)-ethanol (0.5 mL)-water (0.5 mL), lithium hydroxide monohydrate (0.012 g) was added, and the mixture was stirred at room temperature for 3 hours. 2 mol/L hydrochloric acid (0.14 mL) was added to the reaction mixture for neutralization, and water was added to the mixture to facilitate Extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

[實施例4] [Example 4] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.040g)之四氫呋喃(1mL)-乙醇(0.5mL)-水(0.5mL)混合液中添加氫氧化鋰一水合物(0.011g)，並於室溫下攪拌3小時。於反應混合物中添加2mol/L鹽酸(0.13mL)進行中和，於該混合物中添加水，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.035g)。 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2) at room temperature -Methylphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.040 g) in tetrahydrofuran (1 mL) To a mixture of ethanol (0.5 mL) and water (0.5 mL), lithium hydroxide monohydrate (0.011 g) was added and stirred at room temperature for 3 hours. 2 mol/L hydrochloric acid (0.13 mL) was added to the reaction mixture for neutralization, and water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

[實施例5] [Example 5] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲氧基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-3-methoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3-甲氧基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.025g)之四氫呋喃(1mL)-乙醇(0.5mL)-水(0.5mL)混合液中添加氫氧化鋰一水合物(0.006g)，並於室溫下攪拌3小時。於反應混合物中添加2mol/L鹽酸(0.075mL)進行中和，於該混合物中添加水，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.021g)。 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2) at room temperature -Methylphenyl)-3-methoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.025 g) in tetrahydrofuran (1 mL Lithium hydroxide monohydrate (0.006 g) was added to a mixture of ethanol (0.5 mL) and water (0.5 mL), and stirred at room temperature for 3 hours. To the reaction mixture, 2 mol/L hydrochloric acid (0.075 mL) was added for neutralization, and water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

[實施例6] [Embodiment 6] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4-fluoro- 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.02g)之四氫呋喃(0.30mL)-甲醇(0.15mL)-水(0.15mL)混合液中添加氫氧化鋰一水合物(0.007g)，並於室溫下攪拌2小時。於反應混合物中添加乙酸進行中和，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.02g)。 [5'-{[2-(3,5-Bis-Trifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'- at room temperature (4-Fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.02 g) in tetrahydrofuran (0.30) To a mixture of methanol (0.15 mL) and water (0.15 mL), lithium hydroxide monohydrate (0.007 g) was added and stirred at room temperature for 2 hours. Acetic acid was added to the reaction mixture for neutralization, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

[實施例7] [Embodiment 7] 2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]-2-甲基丙酸 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methyl Phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]-2-methylpropionic acid

於微波照射下將2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]-2-甲基丙酸乙酯(0.14g)、氫氧化鈉水溶液(1.0mol/L，0.60mL)、四氫呋喃(0.6mL)及甲醇(1.8mL)之混合物於140℃下攪拌4.5小時。於反應混合物中添加氫氧化鈉水溶液(2.0mol/L，0.50mL)，並於微波照射下於140℃下攪拌2小時。將反應混合物冷卻至室溫後，添加鹽酸(1.0mol/L，2.0mL)，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗後，利用無水硫酸鎂進行乾燥，並於減壓下蒸餾去除，而獲得標題化合物(0.11g)。 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropenyl]methylamino}-4'-(4-fluoro) under microwave irradiation 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]-2-methylpropanoic acid ethyl ester (0.14 g), hydrogen A mixture of a sodium oxide aqueous solution (1.0 mol/L, 0.60 mL), tetrahydrofuran (0.6 mL) and methanol (1.8 mL) was stirred at 140 ° C for 4.5 hours. An aqueous sodium hydroxide solution (2.0 mol/L, 0.50 mL) was added to the reaction mixture, and the mixture was stirred at 140 ° C for 2 hours under microwave irradiation. After cooling the reaction mixture to room temperature, hydrochloric acid (1.0 mol/L, 2.0 mL) was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.

[實施例8] [Embodiment 8] 2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4- Fluor-2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid

於室溫下於2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸乙酯(0.03g)之四氫呋喃(0.4mL)-甲醇(0.2mL)-水(0.2mL)混合液中添加氫氧化鋰一水合物(0.008g)，並於室溫下攪拌整夜。於反應混合物中添加乙酸進行中和，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯/甲醇=50/50/0~0/100/0~0/90/10)對所獲得之粗產物進行純化，而獲得標題化合物(0.02g)。 2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4 at room temperature '-(4-Fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid ethyl ester (0.03 g) Lithium hydroxide monohydrate (0.008 g) was added to a mixture of tetrahydrofuran (0.4 mL)-methanol (0.2 mL)-water (0.2 mL) and stirred at room temperature overnight. Acetic acid was added to the reaction mixture for neutralization, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product obtained is purified by a ruthenium column chromatography (solvent solvent: n-hexane/ethyl acetate/methanol=50/50/0~0/100/0~0/90/10). The title compound (0.02 g).

[實施例9] [Embodiment 9] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2-methylphenyl )-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.03g)、四氫呋喃(0.375mL)、甲醇(0.375mL)及水(0.15mL)之混合物中添加氫氧化鋰一水合物(0.02g)，並於室溫下攪拌3小時，於50℃下攪拌4小時。將反應混合物冷卻至室溫後，添加鹽酸(2.0mol/L，0.2mL)，利用乙酸乙酯進行萃取。將有機層利用水、飽和鹽水清洗，並利用無水硫酸鈉進行乾燥後，於減壓下蒸餾去除，而獲得標題化合物(0.025g)。 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro-2) at room temperature -methylphenyl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.03 g), tetrahydrofuran (0.375 mL) Lithium hydroxide monohydrate (0.02 g) was added to a mixture of methanol (0.375 mL) and water (0.15 mL), and stirred at room temperature for 3 hours and at 50 ° C for 4 hours. After cooling the reaction mixture to room temperature, hydrochloric acid (2.0 mol/L, 0.2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate.

[實施例10] [Embodiment 10] [5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸 [5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'-(4-fluoro- 2-methylphenyl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetic acid

於室溫下於[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-6'-氰基-4'-(4-氟-2-甲基苯基)-4-甲基-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]乙酸乙酯(0.06g)、四氫呋喃(0.50mL)、甲醇(0.25mL)及水(0.25mL)之混合物中添加氫氧化鋰一水合物(0.02g)，並於室溫下攪拌1小時，於50℃下攪拌3小時。將反應混合物冷卻至室溫後，添加乙酸進行中和，利用乙酸乙酯進行萃取。將有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯/甲醇=20/80/0~0/100/0~0/90/10)對所獲得之粗產物進行純化，而獲得標題化合物(0.03g)。 [5'-{[2-(3,5-Bis-Trifluoromethylphenyl)-2-methylpropanyl]methylamino}-6'-cyano-4'- at room temperature (4-Fluoro-2-methylphenyl)-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]acetate (0.06 g Lithium hydroxide monohydrate (0.02 g) was added to a mixture of tetrahydrofuran (0.50 mL), methanol (0.25 mL) and water (0.25 mL), and stirred at room temperature for 1 hour and at 50 ° C for 3 hours. . After cooling the reaction mixture to room temperature, acetic acid was added for neutralization, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product obtained is purified by a ruthenium column chromatography (solvent solvent: n-hexane/ethyl acetate/methanol=20/80/0~0/100/0~0/90/10). The title compound (0.03 g).

[實施例11] [Example 11] (S)-2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸 (S)-2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro- 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid

於冰浴冷卻下於N-[4-[(S)-2-((S)-4-苄基-2-氧代唑啶-3-基)-1-甲基-2-氧代乙基]-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基]-2-(3,5-雙三氟甲基苯基)-N-甲基異丁基醯胺(0.08g)之四氫呋喃(1.5mL)-水(0.5mL)混合液中添加氫氧化鋰一水合物(0.008g)及過氧化氫水(30%，0.06mL)，並於該溫度下攪拌整夜。於反應混合物中添加亞硫酸鈉水溶液(10%，0.75mL)，並攪拌30分鐘。將溶劑於減壓下濃縮，於殘渣中添加鹽酸(1.0mol/L)而設為酸性，利用乙酸乙酯進行萃取。利 用乙酸乙酯再萃取水層，將所合併之有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~10/90)對所獲得之粗產物進行純化，而獲得標題化合物(0.014g)。 N-[4-[(S)-2-((S)-4-benzyl-2-oxo) under ice cooling Zoxadin-3-yl)-1-methyl-2-oxoethyl]-4'-(4-fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H- [1,2']bipyridyl-5'-yl]-2-(3,5-bistrifluoromethylphenyl)-N-methylisobutylguanamine (0.08 g) in tetrahydrofuran (1.5 mL) To a mixed solution of water (0.5 mL), lithium hydroxide monohydrate (0.008 g) and hydrogen peroxide water (30%, 0.06 mL) were added, and stirred at this temperature overnight. An aqueous solution of sodium sulfite (10%, 0.75 mL) was added to the mixture and stirred for 30 min. The solvent was concentrated under reduced pressure, and hydrochloric acid (1.0 mol/L) was added to the residue to be acidic, and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:

[實施例12] [Embodiment 12] (R)-2-[5'-{[2-(3,5-雙三氟甲基苯基)-2-甲基丙醯基]甲基胺基}-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-4-基]丙酸 (R)-2-[5'-{[2-(3,5-bistrifluoromethylphenyl)-2-methylpropanyl]methylamino}-4'-(4-fluoro- 2-methylphenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyridin-4-yl]propionic acid

於冰浴冷卻下於N-[4-[(R)-2-((S)-4-苄基-2-氧代唑啶-3-基)-1-甲基-2-氧代乙基]-4'-(4-氟-2-甲基苯基)-3,4,5,6-四氫-2H-[1,2']聯吡啶-5'-基]-2-(3,5-雙三氟甲基苯基)-N-甲基異丁基醯胺(0.04g)之四氫呋喃(0.75mL)-水(0.25mL)混合液中添加氫氧化鋰一水合物(0.004g)及過氧化氫水(30%，0.03mL)，並於該溫度下攪拌7小時。於反應混合物中添加亞硫酸鈉水溶液(10%，0.375mL)，並攪拌30分鐘。將溶劑於減壓下濃縮，於殘渣中添加鹽酸(1.0mol/L)而設為酸性，利用乙酸乙酯進行萃取。利用乙酸乙酯再萃取水層，將所合併之有機層利用飽和鹽水清洗，並利用無水硫酸鎂進行乾燥後，於減壓下蒸餾去除。藉由矽膠管柱層析法(溶出溶劑：正己烷/乙酸乙酯=90/10~10/90)對所獲得之粗產物進行純化，而獲得標題化合物(0.004g)。 N-[4-[(R)-2-((S)-4-benzyl-2-oxo) under ice cooling Zoxadin-3-yl)-1-methyl-2-oxoethyl]-4'-(4-fluoro-2-methylphenyl)-3,4,5,6-tetrahydro-2H- [1,2']bipyridyl-5'-yl]-2-(3,5-bistrifluoromethylphenyl)-N-methylisobutylguanamine (0.04 g) in tetrahydrofuran (0.75 mL) To a mixed solution of water (0.25 mL), lithium hydroxide monohydrate (0.004 g) and hydrogen peroxide water (30%, 0.03 mL) were added, and stirred at this temperature for 7 hours. Aqueous sodium sulfite solution (10%, 0.375 mL) was added to the mixture and stirred for 30 min. The solvent was concentrated under reduced pressure, and hydrochloric acid (1.0 mol/L) was added to the residue to be acidic, and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained was purified by EtOAc EtOAc (EtOAc:EtOAc:

將上述參考例1~32之化學結構式、以及實施例1~12之化學結構式、及物性值示於表1~7。關於表中之縮寫，Ref.Mo.表示參考例編號，Ex.No.表示實施例編號，Str.表示化學結構式，Physical data表示物性值，1H-NMR表示氫核核磁共振譜，DMSO-d6表示二甲基亞碸-d6，CDCl3表示氯仿-d1。又，MS表示質譜分析，ESI_APCI表示藉由電灑離子化法-大氣壓化學離子化法之多離子化法進行測定。 The chemical structural formulae of the above Reference Examples 1 to 32, and the chemical structural formulas and physical property values of Examples 1 to 12 are shown in Tables 1 to 7. Regarding the abbreviations in the table, Ref. Mo. indicates a reference example number, Ex. No. indicates an example number, Str. indicates a chemical structural formula, Physical data indicates a physical property value, and 1 H-NMR indicates a hydrogen nuclear magnetic resonance spectrum, DMSO- D6 represents dimethyl azine-d6, and CDCl 3 represents chloroform-d1. Further, MS indicates mass spectrometry, and ESI_APCI indicates measurement by a multi-ionization method by electrospray ionization-atmospheric pressure chemical ionization.

[試驗例1] [Test Example 1] 對人類NK1受體之親和性 Affinity to human NK 1 receptor (1)人類NK1受體表現載體之製備 (1) Preparation of human NK 1 receptor expression vector

將源自人類成人正常組織之腦互補脫氧核糖核酸(cDNA，complementary deoxyribonucleic acid)(BioChain)作為模板，使用序列編號1所示之前置引子、序列編號2所示之反置引子，藉由聚合酶鏈鎖反應(PCR，Polymerase Chain Reaction)酶PrimeSTAR Max DNA聚合酶或PrimeSTAR GXL DNA聚合酶(註冊商標，TAKARA BIO)而實施PCR。使用Zero Blunt PCR選殖試劑套組(註冊商標，Life Technologies)將擴增產物組入至質體(pCR-BluntII-TOPO(註冊商標)，Life Technologies)中。藉由常法，使用組入有擴增產物之質體使大腸桿菌(One Shot TOP10勝任細胞，Life Technologies)轉形。將該大腸桿菌於含有50μg/mL之康黴素之LB瓊脂培養基中培養1天。於培養後，選擇菌落，並於含有50μg/mL之康黴素之LB培養基中進行培養。於培養後，使用Quantum Prep質體微量純化套組(Bio-Rad)將質體純化。利用限制酶XhoI及HindIII(New England Biolabs)使該質體雙重消化約2小時後，進行1%瓊脂糖電泳，並使用TaKaRa RICOCHIP(TAKARA BIO)將經切斷之片段回收、純化。另外亦由藉由載體(pcDNA3.1(-)(註冊商標)，Life Technologies)而轉形之大腸桿菌純化質體，並利用限制酶XhoI及HindIII(New England Biolabs)使其雙重消化約2小時後，進行1%瓊脂糖電泳，使用TaKaRa RICOCHIP(TAKARA BIO)將經切斷之載體回收、純化。使用DNA接合試劑套組<Mighty Mix>(TAKARA BIO)使自pCR-Blunt-II切斷之片段與經限制酶處理之pcDNA3.1(-)載體進行接 合反應。使用接合後之質體，藉由常法使大腸桿菌(One Shot TOP10勝任細胞，Life Technologies)轉形。將該大腸桿菌於含有50μg/mL之安比西林之溶菌肉湯(LB，lysogeny broth)瓊脂培養基中培養1天。於培養後，選擇菌落，並於含有50μg/mL之安比西林之LB培養基中進行培養，其後，使用Quantum Prep質體微量純化套組(Bio-Rad)將質體純化。編碼所獲得之質體之蛋白質之鹼基序列(序列編號3)與公知之資料庫(NCBI)中所登錄之人類速激肽受體1(TACR1，NK1R)之鹼基序列(NM_001058.3)完全一致。因此，確認所選殖之基因序列為人類NK1受體之鹼基序列，所轉譯之胺基酸序列為人類NK1受體。將***有序列編號3所示之鹼基序列之pcDNA3.1(-)(註冊商標)作為人類NK1受體表現質體。 Using a complementary deoxyribonucleic acid (BioChain) derived from human adult normal tissues as a template, using the reverse primer shown in SEQ ID NO: 1, and the reverse primer shown in SEQ ID NO: 2, by polymerization PCR was carried out by a PCR (Polymerase Chain Reaction) enzyme PrimeSTAR Max DNA polymerase or PrimeSTAR GXL DNA polymerase (registered trademark, TAKARA BIO). The amplified product was incorporated into the plastid (pCR-BluntII-TOPO (registered trademark), Life Technologies) using the Zero Blunt PCR Colony Kit (registered trademark, Life Technologies). Escherichia coli (One Shot TOP10 Competent Cell, Life Technologies) was transformed by a conventional method using a plastid into which an amplification product was incorporated. The Escherichia coli was cultured for 1 day in an LB agar medium containing 50 μg/mL of oxytetracycline. After the cultivation, colonies were selected and cultured in LB medium containing 50 μg/mL of oxytetracycline. After incubation, the plastids were purified using the Quantum Prep plastid micropurification kit (Bio-Rad). The plastid was double-digested with restriction enzymes XhoI and HindIII (New England Biolabs) for about 2 hours, subjected to 1% agarose electrophoresis, and the cut fragment was recovered and purified using TaKaRa RICOCHIP (TAKARA BIO). The plastid was also purified from E. coli transformed by a vector (pcDNA3.1 (-) (registered trademark), Life Technologies), and double-digested with restriction enzymes XhoI and HindIII (New England Biolabs) for about 2 hours. Thereafter, 1% agarose electrophoresis was carried out, and the cleaved vector was recovered and purified using TaKaRa RICOCHIP (TAKARA BIO). The fragment cleaved from pCR-Blunt-II was subjected to a ligation reaction with a restriction enzyme-treated pcDNA3.1 (-) vector using a DNA ligation reagent kit <Mighty Mix> (TAKARA BIO). Escherichia coli (One Shot TOP10 Competent Cell, Life Technologies) was transformed by the usual method using the plastid after the joining. The Escherichia coli was cultured for 1 day in a lysogeny broth agar medium containing 50 μg/mL of ampicillin. After the cultivation, colonies were selected and cultured in LB medium containing 50 μg/mL of ampicillin, after which the plastids were purified using a Quantum Prep plastid micropurification kit (Bio-Rad). The base sequence of the protein encoding the obtained plastid (SEQ ID NO: 3) and the base sequence of human tachykinin receptor 1 (TACR1, NK1R) registered in the well-known database (NCBI) (NM_001058.3) It is exactly the same. Therefore, it was confirmed that the selected gene sequence is the base sequence of the human NK 1 receptor, and the translated amino acid sequence is the human NK 1 receptor. The pcDNA3.1(-) (registered trademark) into which the nucleotide sequence shown in SEQ ID NO: 3 was inserted was expressed as a human NK 1 receptor.

(2)人類NK1受體表現細胞之製備 (2) Preparation of human NK 1 receptor expressing cells (2-1)293T細胞之培養 (2-1) Cultivation of 293T cells

293T細胞(理化學研究所)係使用添加有抗生素青黴素-鏈黴素溶液(Race Technologies，最終濃度：以青黴素計為100U/mL，鏈黴素100μg/mL)及胎牛血清(最終濃度：10%)之杜爾伯科改良伊格爾培養基(D-MEM，Dulbecco's Modified Eagle Medium)之液體培養基(低葡萄糖，含有L-麩醯胺，和光純藥工業)，於5%CO2氣體條件之培養箱內於37℃下進行培養。 293T cells (Institute of Physical Chemistry) were supplemented with an antibiotic penicillin-streptomycin solution (Race Technologies, final concentration: 100 U/mL in penicillin, streptomycin 100 μg/mL) and fetal bovine serum (final concentration: 10 %) Dulmeco's Modified Eagle Medium (D-MEM, Dulbecco's Modified Eagle Medium) liquid medium (low glucose, containing L-bromoamide, and Wako Pure Chemical Industries), under 5% CO 2 gas conditions The culture was carried out at 37 ° C in an incubator.

(2-2)293T細胞之繼代 (2-2) Subculture of 293T cells

利用磷酸鹽緩衝液(PBS，Phosphate Buffered Saline，和光純藥工業)清洗幾乎達到融合之細胞，利用0.05%胰蛋白酶-乙二胺四乙酸(EDTA，ethylenediaminetetraacetic acid)(Race Technologies)將其剝離， 並懸浮於上述液體培養基中。將懸浮之細胞以散佈度成為1：10之方式利用上述液體培養基進行稀釋並培養。 The fused cells were washed with phosphate buffer (PBS, Phosphate Buffered Saline, and Wako Pure Chemical Industries, Ltd.), and exfoliated with 0.05% trypsin-ethylenediaminetetraacetic acid (EDTA). And suspended in the above liquid medium. The suspended cells were diluted and cultured using the above liquid medium in such a manner that the degree of dispersion was 1:10.

(2-3)人類NK1受體表現細胞之準備 (2-3) Preparation of human NK 1 receptor expressing cells

利用PBS清洗達到融合之細胞，利用0.05%胰蛋白酶-EDTA(Race Technologies)將其剝離，並懸浮於添加有胎牛血清(最終濃度：10%)之D-MEM液體培養基(低葡萄糖，含有L-麩醯胺，和光純藥工業)中。將懸浮之細胞利用上述液體培養基進行稀釋，以細胞數5×104個/孔、液體培養基量為100μL/孔之方式製備並接種至塗佈有聚D-離胺酸之96孔微板(BD Biocoat(註冊商標)，Nippon Becton Dickinson)之各孔。於接種後，將該細胞於5%CO2氣體條件之培養箱內於37℃下培養約4~5小時，而製成人類NK1受體表現質體導入用細胞。 The fused cells were washed with PBS, exfoliated with 0.05% trypsin-EDTA (Race Technologies), and suspended in D-MEM liquid medium (low glucose, containing L) supplemented with fetal bovine serum (final concentration: 10%). - branamine, and light pure drug industry). The suspension of cells was diluted using the liquid medium, the number of 5 × 10 4 cells / well, the amount of liquid medium from the cells to poly-D- embodiment was prepared and seeded 100 L / well of leucine to the coating of 96-well microplate ( Each hole of BD Biocoat (registered trademark), Nippon Becton Dickinson). After the inoculation, the cells were cultured in an incubator at 5% CO 2 atmosphere at 37 ° C for about 4 to 5 hours to prepare a human NK 1 receptor for expressing plastid-importing cells.

(2-4)人類NK1受體表現質體向293T細胞之導入 (2-4) Human NK 1 receptor shows the introduction of plastids into 293T cells

為了導入人類NK1受體表現質體，使用脂染胺2000(註冊商標，Life Technologies)。將人類NK1受體表現質體以成為0.2μg/25μL/孔之方式利用Opti-MEM(註冊商標)I低血清培養基(Life Technologies)進行稀釋。同時，將脂染胺2000(註冊商標，Life Technologies)以成為0.4μL/25μL/孔之方式利用Opti-MEM(註冊商標)I低血清培養基(Life Technologies)進行稀釋，並於室溫下培養5分鐘。5分鐘後，為了形成人類NK1受體表現質體/脂染胺2000之複合體，將經稀釋之人類NK1受體表現質體與經稀釋之脂染胺2000混合，並於室溫下培養20~25分鐘。於培養後，將複合體液以50μL/孔添加至上述人類NK1受體表現質體導入用細胞，並於5%CO2氣體條件之培養箱內於37℃下培養約48小時。將該培養48小時後之細胞作為人類NK1受體表現細胞並用於各種分析。 In order to introduce a human NK 1 receptor to express a plastid, a lipofectamine 2000 (registered trademark, Life Technologies) was used. The human NK 1 receptor expressing plastid was diluted with Opti-MEM (registered trademark) I low serum medium (Life Technologies) in a manner of 0.2 μg / 25 μL / well. At the same time, lipofectamine 2000 (registered trademark, Life Technologies) was diluted with Opti-MEM (registered trademark) I low serum medium (Life Technologies) in a manner of 0.4 μL / 25 μL / well, and cultured at room temperature. minute. After 5 minutes, in order to form the human NK 1 receptor expression plasmid / lipid lipofectamine 2000 complex, the expression plasmid with the diluted lipofectamine 2000 of lipid mixing the diluted human NK 1 receptor, and at room temperature Cultivate for 20 to 25 minutes. After the culture, the complex liquid was added to the human NK 1 receptor-expressing plastid-importing cells at 50 μL/well, and cultured at 37 ° C for about 48 hours in an incubator of 5% CO 2 gas. The cells after 48 hours of culture were used as human NK 1 receptor-expressing cells and used for various analyses.

(3)人類NK1受體結合親和性之測定 (3) Determination of human NK 1 receptor binding affinity (3-1)自人類NK1受體表現細胞之膜組分之製備 (3-1) Preparation of membrane fractions from human NK 1 receptor expressing cells

於175cm2培養燒瓶(Nippon Becton Dickinson)內製作人類NK1受體表現細胞。人類NK1受體表現質體與脂染胺2000之複合體形成反應係根據上述2-4中記載之方法藉由培養面積之比率計算進行規模放大而實施。利用膜組分製備用緩衝液(50mM三羥甲基胺基甲烷(和光純藥工業)、120mM氯化鈉(和光純藥工業)、5mM氯化鉀(和光純藥工業)、1mM乙二胺四乙酸(Sigma)、0.002mg/mL胰凝乳蛋白酶抑制劑(PEPTIDE INSTITUTE)、0.04mg/桿菌肽(和光純藥工業)、0.005mg/mL膦醯二肽(PEPTIDE INSTITUTE)、0.5mM苯基甲基磺醯氟(和光純藥工業)，pH值7.4)回收人類NK1受體表現細胞，利用1,880g進行10分鐘離心分離，並使細胞沈渣懸浮於膜組分製備用緩衝液中。進行1次凍結融解後，使用Dounce型均質機(於冰浴冷卻下，1000rpm，20次)使細胞破碎。對破碎之細胞懸浮液以20,000rpm進行10分鐘離心分離，捨棄上清液而獲得細胞沈渣。使細胞沈渣再懸浮於膜組分製備用緩衝液中之後，使用Dounce型均質機(於冰浴冷卻下，1000rpm，30次)使其破碎，對細胞懸浮液以20,000rpm進行10分鐘離心分離，捨棄上清液而獲得細胞沈渣。再次重複相同之破碎與離心分離操作，而獲得最終細胞沈渣。使最終細胞沈渣懸浮於受體結合試驗用緩衝液(50mM三羥甲基胺基甲烷(和光純藥工業)、3mM氯化錳(和光純藥工業)、0.002mg/mL胰凝乳蛋白酶抑制劑(PEPTIDE INSTITUTE)、0.04mg/桿菌肽(和光純藥工業)、0.02%牛血清白蛋白(Sigma)，pH值7.4)中，並使用二辛可寧酸(BCA，bicinchoninic acid)蛋白質分析套組(Pierce)測定蛋白質濃度。 Human NK 1 receptor expressing cells were prepared in a 175 cm 2 culture flask (Nippon Becton Dickinson). The human NK 1 receptor-expressing complex formation reaction between the plastid and the lipofectamine 2000 is carried out by scale-up calculation by the ratio of the culture area according to the method described in the above 2-4. The membrane component preparation buffer (50 mM trishydroxymethylaminomethane (Wako Pure Chemical Industries, Ltd.), 120 mM sodium chloride (Wako Pure Chemical Industries, Ltd.), 5 mM potassium chloride (Wako Pure Chemical Industries, Ltd.), 1 mM ethylenediamine Tetraacetic acid (Sigma), 0.002 mg/mL chymotrypsin inhibitor (PEPTIDE INSTITUTE), 0.04 mg/bacillus peptide (Wako Pure Chemical Industries, Ltd.), 0.005 mg/mL phosphine dipeptide (PEPTIDE INSTITUTE), 0.5 mM phenyl Methylsulfonium fluoride (Wako Pure Chemical Industries, Ltd., pH 7.4) was used to recover human NK 1 receptor-expressing cells, which were centrifuged for 10 minutes using 1,880 g, and the cell sediment was suspended in a buffer for membrane component preparation. After one freeze-thaw, the cells were disrupted using a Dounce-type homogenizer (1000 rpm, 20 times under ice cooling). The disrupted cell suspension was centrifuged at 20,000 rpm for 10 minutes, and the supernatant was discarded to obtain cell sediment. After the cell sediment was resuspended in the buffer for the preparation of the membrane component, it was disrupted using a Dounce-type homogenizer (1000 rpm under ice-cooling), and the cell suspension was centrifuged at 20,000 rpm for 10 minutes. The supernatant was discarded to obtain cell sediment. The same disruption and centrifugation operations were repeated again to obtain final cell sediment. The final cell sediment was suspended in a receptor binding assay buffer (50 mM trishydroxymethylaminomethane (Wako Pure Chemical Industries, Ltd.), 3 mM manganese chloride (Wako Pure Chemical Industries), 0.002 mg/mL chymotrypsin inhibitor (PEPTIDE INSTITUTE), 0.04 mg/bacillus peptide (Wako Pure Chemical Industries), 0.02% bovine serum albumin (Sigma), pH 7.4), and using BCA (bicinchoninic acid) protein analysis kit (Pierce) Determine the protein concentration.

(3-2)受體結合試驗 (3-2) Receptor binding assay

對96孔分析板(Greiner)以22.5μL/孔分注上述受體結合試驗用緩衝液，以2.5μL/孔(最終濃度：1nM~100nM)添加利用100%二甲基亞碸(DMSO)製備為80倍濃度之試驗化合物DMSO溶液並進行混合。放射性標記配位子係使用125I-P物質(Substance P，[125I]Tyr8-，PerkinElmer)。將125I-P物質以成為125pmol/25μL/孔之方式利用受體結合試驗用緩衝液進行稀釋，將其添加至96孔分析板並進行混合。將由人類NK1受體表現細胞所製備之膜組分以成為8~10μg/孔之方式利用受體結合試驗用緩衝液進行稀釋，使其均勻地懸浮直至可順利地通過27G之注射針，並以150μL/孔添加至96孔分析板，一面於室溫下振盪60分鐘一面進行培養。利用經0.3%聚伸乙亞胺預處理之MultiScreen 96孔濾板(Millipore)將反應液抽吸過濾，並利用清洗液(50mM三羥甲基胺基甲烷、0.02%牛血清白蛋白，pH值7.4)清洗4次，藉此結束反應。以60℃使微板底部乾燥後，以100μL/孔分注Micro-Scint 20(PerkinElmer)，利用TopSeal A(PerkinElmer)將板上部栓緊，並振盪5~10分鐘，其後，利用TopCount NXT(註冊商標)(PerkinElmer)測定放射活性。各孔之放射活性係藉由減去添加10μM之阿瑞吡坦時之放射活性(非特異性結合)而算出。算出125I-P物質之結合率%=(試驗化合物添加群組之放射活性)/(介質添加群組之放射活性)×100，使用解析軟體GraphPad Prism(GraphPad Software)對結合率%相對於試驗化合物濃度之曲線進行直線近似，算出50%抑制濃度IC50。將該等結果示於表8。表中，Ex.No.表示實施例編號，IC50(nM)表示50%抑制濃度。 The above-mentioned receptor binding assay buffer was dispensed into a 96-well assay plate (Greiner) at 22.5 μL/well, and prepared by adding 100% dimethyl sulfoxide (DMSO) at 2.5 μL/well (final concentration: 1 nM to 100 nM). The test compound DMSO solution was 80 times the concentration and mixed. The radiolabeled ligand system used 125 IP material (Substance P, [ 125 I] Tyr 8 -, PerkinElmer). The 125 IP substance was diluted with the receptor binding assay buffer in such a manner as to become 125 pmol/25 μL/well, which was added to a 96-well assay plate and mixed. The membrane component prepared by the human NK 1 receptor-expressing cells is diluted with the receptor binding assay buffer in a manner of 8 to 10 μg/well, and uniformly suspended until it can smoothly pass through the 27G injection needle, and The cells were added to a 96-well assay plate at 150 μL/well, and cultured while shaking at room temperature for 60 minutes. The reaction solution was suction filtered using a MultiScreen 96-well filter plate (Millipore) pretreated with 0.3% polyethylenimine, and a washing solution (50 mM trishydroxymethylaminomethane, 0.02% bovine serum albumin, pH value) was used. 7.4) Wash 4 times to end the reaction. After drying the bottom of the microplate at 60 ° C, Micro-Scint 20 (PerkinElmer) was dispensed at 100 μL/well, and the upper portion was tightened with TopSeal A (PerkinElmer) and shaken for 5 to 10 minutes, after which, the TopCount NXT was used ( Radioactive activity was determined by registered trademark (PerkinElmer). The radioactivity of each well was calculated by subtracting the radioactivity (non-specific binding) when 10 μM of aprepitant was added. Calculate the binding rate of 125 IP substance% = (radiation activity of the test compound addition group) / (radioactivity of the medium addition group) × 100, using the analytical software GraphPad Prism (GraphPad Software), the binding rate % versus the test compound concentration The curve was approximated by a straight line to calculate a 50% inhibitory concentration IC 50 . The results are shown in Table 8. In the table, Ex. No. indicates an example number, and IC 50 (nM) indicates a 50% inhibitory concentration.

(4)結果 (4) Results

[表8] [Table 8]

如表8所示，明確本發明之化合物對人類NK1受體顯示較高之結合親和性。 As shown in Table 8, it was confirmed that the compound of the present invention showed high binding affinity to the human NK 1 receptor.

[試驗例2] [Test Example 2] 對人類NK1受體之抑制作用 Inhibition of human NK 1 receptor (1)人類NK1受體表現細胞之製備 (1) Preparation of human NK 1 receptor expressing cells

藉由與試驗例1之2-3及2-4相同之方法進行製作。 The production was carried out in the same manner as in Tests 1 to 2-3 and 2-4.

(2)細胞內鈣濃度上升抑制作用之研究 (2) Study on the inhibition of intracellular calcium concentration increase

利用清洗液(20mM羥乙基哌乙磺酸(HEPES，hydroxyethyl piperazineethanesulfonic acid)/漢克平衡鹽溶液(HBSS，Hank's Balanced Salt Solution)pH值7.3)以300μL/孔清洗人類NK1受體表現細胞。將螢光鈣指示劑(Fluo-4 Direct鈣分析套組，Life Technologies，含有0.42mM丙磺舒及含有0.1%牛血清白蛋白：藉由該製品操作說明而製備)以150μL/孔添加至各孔，並於37℃下於培養箱內培養30分鐘。其後，以2.5μL/孔(最終濃度：0.1、1、10μM)添加利用100%二甲基亞碸(DMSO)製備為80倍濃度之試驗化合物DMSO溶液並進行混合，其後，進而於37℃下於培養箱內培養30分鐘。30分鐘後迅速測定細胞內鈣濃度。 細胞內鈣濃度係使用FDSS(註冊商標)7000(Hamamatsu Photonics)作為螢光訊號而測定。螢光訊號係自讀取開始10秒後以50μL/孔(最終濃度：0.1或1μM)自動添加利用分析緩衝液(20mM HEPES/漢克平衡鹽溶液(HBSS)pH值7.3，含有0.1%牛血清白蛋白)製備為0.4μM或4μM的P物質(PEPTIDE INSTITUTE)溶液，並測定至120秒為止。將添加有介質(DMSO)之群組之螢光訊號設為100%，將添加P物質前之螢光訊號設為0%，藉由下式而算出添加各試驗化合物時之細胞內鈣濃度%。 Use cleaning solution (20mM hydroxyethylperidazole Hexane sulfonate (HEPES, hydroxyethyl piperazineethanesulfonic acid) / Hank's Balanced Salt Solution (pH 7.3) washed human NK 1 receptor-expressing cells at 300 μL/well. Fluorescent calcium indicator (Fluo-4 Direct calcium assay kit, Life Technologies, containing 0.42 mM probenecid and containing 0.1% bovine serum albumin: prepared by the product instructions) was added to each at 150 μL/well The wells were incubated at 37 ° C for 30 minutes in an incubator. Thereafter, a test compound DMSO solution prepared by using 100% dimethyl hydrazine (DMSO) at a concentration of 80 times was added at 2.5 μL/well (final concentration: 0.1, 1, 10 μM), followed by mixing, and further, at 37. Incubate in an incubator at °C for 30 minutes. The intracellular calcium concentration was quickly determined after 30 minutes. The intracellular calcium concentration was measured using FDSS (registered trademark) 7000 (Hamamatsu Photonics) as a fluorescent signal. The fluorescent signal was automatically added at 50 μL/well (final concentration: 0.1 or 1 μM) from the start of reading for 10 seconds using assay buffer (20 mM HEPES/Hanke Balanced Salt Solution (HBSS) pH 7.3, containing 0.1% bovine serum Albumin) was prepared as a 0.4 μM or 4 μM P substance (PEPTIDE INSTITUTE) solution and measured to 120 seconds. The fluorescence signal of the group to which the medium (DMSO) was added was set to 100%, and the fluorescence signal before the addition of the substance P was set to 0%, and the intracellular calcium concentration at the time of adding each test compound was calculated by the following formula. .

細胞內鈣濃度%=(試驗化合物添加群組之螢光訊號)/(介質添加群組之螢光訊號)×100 Intracellular calcium concentration%=(fluorescent signal of test compound addition group)/(fluorescent signal of medium addition group)×100

將該細胞內鈣濃度%設為P物質之促效劑活性之殘留活性(SPRR，Substance P-Response Remaining)。將該等結果示於表9。表中，Ex.No.表示實施例編號，SPRR(%)表示P物質濃度為1μM、化合物濃度為0.1μM時之結果。 The intracellular calcium concentration % was defined as the residual activity of the agonist activity of the substance P (SPRR, Substance P-Response Remaining). These results are shown in Table 9. In the table, Ex. No. indicates the example number, and SPRR (%) indicates the result when the concentration of the substance P was 1 μM and the concentration of the compound was 0.1 μM.

(3)結果 (3) Results

如表9所示，明確本發明之化合物顯示人類NK1受體拮抗作用。 As shown in Table 9, it was confirmed that the compound of the present invention showed human NK 1 receptor antagonism.

[試驗例3] [Test Example 3] 對CYP3A4之抑制作用 Inhibition of CYP3A4

製備評價濃度之1000倍濃度之試驗化合物之二甲基亞碸(DMSO)溶液，並將其稀釋而製備反應溶液。於包含1nM~20μM試驗化合物、3.2mM氯化鎂、0.2pmol人類CYP3A4(BD Biosciences)、0.5mM還原型菸鹼醯胺腺嘌呤雙核苷酸磷酸(NADPH)、及3μM螢光素-乙酸異丙烯酯(IPA，isopropenyl acetate)(Promega)的磷酸鉀緩衝液(pH值7.4)中於37℃下培養10分鐘，藉此進行酶反應。以反應液量為50μL/孔進行。30分鐘預培養群組係於添加作為基質之螢光素-IPA溶液(12.5μL/孔)前，於37℃下培養30分鐘。於酶反應結束時，添加50μL/孔之螢光素檢測試劑(Promega)並於室溫下放置20分鐘，其後，利用infinite M1000(TECAN)測定發光強度。算出相對於未添加試驗化合物群組之酶活性(%)，使用解析軟體GraphPad Prism(GraphPad Software)製作劑量反應曲線，並算出顯示50%之抑制之化合物濃度IC50。作為比較例，以同樣之方式對作為NK1受體拮抗劑之阿瑞吡坦進行試驗。 A solution of a test compound in dimethylammonium (DMSO) at a concentration of 1000 times the concentration was prepared and diluted to prepare a reaction solution. Containing 1 nM to 20 μM test compound, 3.2 mM magnesium chloride, 0.2 pmol human CYP3A4 (BD Biosciences), 0.5 mM reduced nicotine indoleamine adenine dinucleotide phosphate (NADPH), and 3 μM luciferin-isopropenyl acetate ( The enzyme reaction was carried out by incubating at 37 ° C for 10 minutes in a potassium phosphate buffer (pH 7.4) of IPA, isopropenyl acetate) (Promega). The reaction liquid amount was 50 μL/well. The 30 minute preculture group was incubated at 37 ° C for 30 minutes before adding the luciferin-IPA solution (12.5 μL/well) as a substrate. At the end of the enzyme reaction, 50 μL/well of luciferin detection reagent (Promega) was added and allowed to stand at room temperature for 20 minutes, after which the luminescence intensity was measured by infinite M1000 (TECAN). A dose response curve was prepared using the analytical software GraphPad Prism (GraphPad Software) with respect to the enzyme activity (%) of the test compound group to be added, and the IC 50 concentration of the compound showing inhibition of 50% was calculated. As a comparative example, aprepitant as an NK 1 receptor antagonist was tested in the same manner.

將利用上述測定方法對試驗化合物之30分鐘預培養群組之IC50值進行測定所得之結果示於表10。表中，Ex.No.表示實施例編號，IC50(μM)表示50%抑制濃度。 The results of measuring the IC 50 value of the 30 minute preculture group of the test compound by the above measurement method are shown in Table 10. In the table, Ex. No. indicates an example number, and IC 50 (μM) indicates a 50% inhibitory concentration.

明確本發明之化合物之CYP3A4之抑制活性與阿瑞吡坦相比得到減弱。因此，期待本發明之化合物與阿瑞吡坦相比基於CYP3A4抑制作用之藥物間相互作用較少。 It is clear that the inhibitory activity of CYP3A4 of the compound of the present invention is attenuated as compared with aprepitant. Therefore, it is expected that the compound of the present invention has less drug-to-drug interaction based on CYP3A4 inhibition than aprepitant.

[試驗例4] [Test Example 4] 對叩足(Foot Tapping)之作用 The role of Foot Tapping (1)對叩足之作用 (1) The role of lameness

利用異氟醚將雄性沙鼠(Japan SLC)麻醉後，自頸靜脈投予試驗化合物0.3mg/kg。4小時後，於異氟醚麻醉下，於頭部前囟之側方1mm、4.5mm深部向腦室內投予作為NK1受體促效劑之GR73632(5pmol/5μl)。於投予後，將沙鼠移至觀察籠中，測定正向反射恢復後5分鐘之引起叩足之時間。試驗化合物之叩足之抑制率(%)係藉由下式而算出。 After anesthetizing male gerbils (Japan SLC) with isoflurane, the test compound was administered from the jugular vein at 0.3 mg/kg. Four hours later, under the isoflurane anesthesia, GR73632 (5 pmol/5 μl), which is an NK 1 receptor agonist, was administered to the ventricle 1 mm and 4.5 mm deep in the lateral side of the head. After the administration, the gerbils were moved to the observation cage, and the time to cause lameness 5 minutes after the recovery of the forward reflex was measured. The inhibition rate (%) of the test compound was calculated by the following formula.

叩足之抑制率(%)={1-(試驗化合物投予之叩足時間)/(溶劑投予之叩足時間)}×100 Inhibition rate of lameness (%) = {1 - (time of lameness of test compound administration) / (time of lamination of solvent administration)} × 100

(2)藥物濃度之測定 (2) Determination of drug concentration

於叩足結束後，迅速於醚麻醉下開腹，自腹部大靜脈採血，同時摘出腦。藉由使用液體層析質譜分析(LC/MS)之定量分析，測定血漿中及腦內之試驗化合物濃度。 After the end of the foot, the laparotomy was quickly performed under ether anesthesia, blood was collected from the abdomen and the brain was removed. The concentration of the test compound in plasma and in the brain was determined by quantitative analysis using liquid chromatography mass spectrometry (LC/MS).

(3)結果 (3) Results

將利用上述試驗方法測定對叩足之作用所得之結果示於表11。表中，Ex.No.表示實施例編號，Inhibition(%)表示叩足之抑制率，Conc.(nM)表示腦內藥物濃度。 The results obtained by measuring the action on the lameness by the above test method are shown in Table 11. In the table, Ex. No. indicates the example number, Inhibition (%) indicates the inhibition rate of the ankle, and Conc. (nM) indicates the concentration of the drug in the brain.

本發明之化合物顯示中樞轉移性，於體內(in vivo)亦表現出優異之NK1受體拮抗作用。 The compounds of the present invention exhibit central metastasis and also exhibit excellent NK 1 receptor antagonism in vivo.

[試驗例5] [Test Example 5] 鼬藥物動態試驗 鼬 drug dynamic test (1)試驗方法 (1) Test method

試驗化合物溶液係溶解於介質(50%N,N-二甲基甲醯胺(和光純藥工業)、30%丙二醇(和光純藥工業)、4%2-羥基丙基-β-環糊精(和光純藥工業))中而製備。於異氟醚麻醉下自頸靜脈對雄性鼬(Marshall BioResources Japan)之靜脈內投予試驗化合物0.3mg/kg。於經口投予之情形時，於清醒下經口投予試驗化合物1mg/kg。於試驗化合物投予後，自前臂橈側皮靜脈隨時間經過進行採血，並藉由使用液體層析質譜分析(LC/MS)之定量分析而測定血漿中之試驗化合物濃度。 The test compound solution was dissolved in a medium (50% N,N-dimethylformamide (Wako Pure Chemical Industries, Ltd.), 30% propylene glycol (Wako Pure Chemical Industries), 4% 2-hydroxypropyl-β-cyclodextrin (Wako Pure Chemical Industries)) prepared in the middle. Male testosterone (Marshall BioResources Japan) was intravenously administered with test compound 0.3 mg/kg under isoflurane anesthesia under isoflurane anesthesia. In the case of oral administration, the test compound was administered orally at a dose of 1 mg/kg under conscious conditions. After the administration of the test compound, blood was collected from the temporal cutaneous vein of the forearm over time, and the concentration of the test compound in the plasma was determined by quantitative analysis using liquid chromatography mass spectrometry (LC/MS).

(2)結果 (2) Results

將利用上述試驗方法實施鼬藥物動態試驗之結果示於表12及表13。表中，Ex.Mo.表示實施例編號，CLtot及Vss分別表示基於靜脈內投予時之血漿中濃度之全身清除率及穩定狀態分佈容積，Cmax、AUC及BA分別表示經口投予時之最高血漿中試驗化合物濃度、血漿中試 驗化合物濃度-時間曲線下面積及生物利用率。 The results of the sputum drug dynamic test conducted by the above test methods are shown in Table 12 and Table 13. In the table, Ex. Mo. indicates the example number, and CLtot and Vss respectively indicate the systemic clearance rate and the steady state distribution volume based on the plasma concentration at the time of intravenous administration, and C max , AUC, and BA indicate the oral administration, respectively. The highest concentration of test compound in plasma, the area under test compound concentration-time curve in plasma, and bioavailability.

如表12及表13所示，本發明之化合物顯示優異之藥物動態。 As shown in Table 12 and Table 13, the compounds of the present invention showed excellent drug dynamics.

[試驗例6] [Test Example 6] 對順鉑誘發急性及遲發性嘔吐反應之作用 Effect of cisplatin on acute and delayed vomiting (1)試驗方法 (1) Test method (1-1)靜脈投予試驗 (1-1) Intravenous administration test

試驗化合物溶液係溶解於介質(50%N,N-二甲基甲醯胺(和光純藥工業)、30%丙二醇(和光純藥工業)、及4%2-羥基丙基-β-環糊精(和光純藥工業)之混合物)中而製備。於對照群組中，僅投予介質。於異氟醚麻醉下自頸靜脈對雄性鼬(Marshall BioResources Japan)之靜脈內投予試驗化合物3mg/kg。自投藥起1小時後向腹腔內投予加溫至40-50℃之順鉑5mg/kg。自順鉑剛投予後至72小時後觀察鼬，並計測乾嘔(無胃內容物之排出之腹部之週期性收縮)及嘔吐之表現次數。 The test compound solution was dissolved in a medium (50% N, N-dimethylformamide (Wako Pure Chemical Industries, Ltd.), 30% propylene glycol (Wako Pure Chemical Industries, Ltd.), and 4% 2-hydroxypropyl-β-cyclodextrin. Prepared in a mixture of fine (Wako Pure Chemical Industries). In the control group, only the medium was administered. Male testosterone (Marshall BioResources Japan) was intravenously administered with test compound 3 mg/kg under isoflurane anesthesia under isoflurane anesthesia. One hour after the administration of the drug, 5 mg/kg of cisplatin heated to 40-50 ° C was administered intraperitoneally. The sputum was observed after 72 hours from the cisplatin administration, and the number of retching (the periodic contraction of the abdomen without the discharge of the stomach contents) and the number of vomiting performances were measured.

(1-2)經口投予試驗 (1-2) Oral administration test

試驗化合物溶液係溶解於介質(1%N-甲基-2-吡咯啶酮、0.5%Tween 80、20%聚乙二醇400、78.5%生理鹽水)中而製備。於對照群組中，僅投予溶劑。對雄性鼬(Marshall BioResources Japan)經口投予試驗化合物。經口投予係每24小時投予1mg/kg進行共計3次。自最初之試驗化合物經口投予起1小時後向腹腔內投予加溫至40-50℃之順鉑5 mg/kg。自順鉑剛投予後至72小時後觀察鼬，並計測乾嘔(無胃內容物之排出之腹部之週期性收縮)及嘔吐之表現次數。 The test compound solution was prepared by dissolving in a medium (1% N-methyl-2-pyrrolidone, 0.5% Tween 80, 20% polyethylene glycol 400, 78.5% physiological saline). In the control group, only the solvent was administered. Test compounds were orally administered to male baboons (Marshall BioResources Japan). Oral administration was carried out by administering 1 mg/kg every 24 hours for a total of 3 times. One hour after the initial administration of the test compound, the cisplatin 5 warmed to 40-50 ° C was intraperitoneally administered. Mg/kg. The sputum was observed after 72 hours from the cisplatin administration, and the number of retching (the periodic contraction of the abdomen without the discharge of the stomach contents) and the number of vomiting performances were measured.

(2)結果 (2) Results

將結果示於圖1。於對照群組中，於急性期(至順鉑投予後24小時為止)及遲發期(順鉑投予後24小時以後至72小時為止)確認到乾嘔及嘔吐之表現次數之增加。於實施例1之化合物靜脈內投予群組及經口投予群組中，於急性期及遲發期確認到乾嘔及嘔吐之表現次數之抑制。明確本發明之化合物顯示優異之藥效持續性、以及對順鉑誘發急性及遲發性嘔吐反應之抑制作用。 The results are shown in Fig. 1. In the control group, an increase in the number of performances of retching and vomiting was confirmed in the acute phase (up to 24 hours after administration of cisplatin) and in the late phase (24 hours after 72 hours after cisplatin administration). In the intravenous administration group and the oral administration group of the compound of Example 1, the inhibition of the number of performances of retching and vomiting was confirmed in the acute phase and the late onset period. It is clear that the compounds of the present invention exhibit excellent drug efficacy persistence and inhibition of cisplatin-induced acute and delayed vomiting.

[試驗例7] [Test Example 7] 對hERG電流之評價 Evaluation of hERG current (1)試驗方法 (1) Test method

製備評價濃度(10μM)之1000倍濃度之試驗化合物之二甲基亞碸(DMSO)溶液，並將其稀釋而製備最終應用濃度之溶液。hERG電流之測定係將接種有表現出hERG通道之人胚腎(HEK，human embryonic kidney)293細胞之覆蓋玻璃放置於灌注槽上並使灌注液流動，藉由使用膜片鉗系統之全細胞法而進行。對藉由資料獲取解析軟體pCLAMP9(Axon Instruments,Inc.)之脈衝協定(保持電位：-80mV，去極化脈衝：+20mV：1.9秒，再極化脈衝：-50mV：2秒，以15秒間隔進行刺激)所產生之源自hERG通道之電流變化進行測定。將測定條件設為流速：約1.5mL/min，溫度：約33℃。對試驗化合物即將應用前及剛應用10分鐘後之各2個波形進行解析，並進行統計解析。將試 驗化合物應用前之值設為100%，求出與該值相比之變化率。 A solution of the test compound in dimethylammonium (DMSO) at a concentration of 1000 times the concentration (10 μM) was prepared and diluted to prepare a solution of the final application concentration. The measurement of hERG current is performed by placing a cover glass inoculated with human embryonic kidney (HEK) 293 cells exhibiting hERG channels on a perfusion tank and flowing the perfusate by a whole cell method using a patch clamp system. And proceed. A pulse agreement for obtaining the analytical software pCLAMP9 (Axon Instruments, Inc.) by data acquisition (holding potential: -80 mV, depolarization pulse: +20 mV: 1.9 seconds, repolarization pulse: -50 mV: 2 seconds, 15 seconds) The change in current originating from the hERG channel generated by the stimulation was measured. The measurement conditions were set to flow rate: about 1.5 mL/min, and temperature: about 33 °C. Two waveforms of the test compound immediately before application and immediately after 10 minutes of application were analyzed and statistical analysis was performed. Will try The value before the application of the test compound was set to 100%, and the rate of change compared with the value was determined.

(2)結果 (2) Results

利用上述方法進行試驗化合物之對hERG電流之評價(將結果示於表14)。表中，Ex.No.表示實施例編號，結果係以平均值±標準誤差來表示。 The test compound was evaluated for hERG current by the above method (the results are shown in Table 14). In the table, Ex. No. indicates the example number, and the results are expressed by the mean value ± standard error.

如表14所示，對於hERG電流，本發明之化合物與介質對照(0.1%DMSO)相比未顯示出統計學上有意義之變動。 As shown in Table 14, for the hERG current, the compounds of the invention showed no statistically significant changes compared to the vehicle control (0.1% DMSO).

(產業上之可利用性) (industrial availability)

本發明之化合物或其藥理學上容許之鹽由於具有優異之NK1受體拮抗作用，故而作為伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之預防或治療劑較為有用。 Since the compound of the present invention or a pharmacologically acceptable salt thereof has excellent NK 1 receptor antagonism, it is useful as a prophylactic or therapeutic agent for nausea and vomiting which is caused by administration of an anti-malignant agent.

序列表自由內容 Sequence table free content

<序列表1> <sequence list 1>

序列編號1係用於使序列編號3之DNA擴增之前置引子之序列。 SEQ ID NO: 1 is a sequence for inserting a primer prior to amplification of the DNA of SEQ ID NO: 3.

<序列表2> <sequence table 2>

序列編號2係用於使序列編號3之DNA擴增之反置引子之序列。 SEQ ID NO: 2 is a sequence of a reverse primer for amplifying the DNA of SEQ ID NO: 3.

<序列表3> <sequence table 3>

序列編號3係以表現人類速激肽受體1之方式使用序列編號1及2之引子而擴增之蛋白質表現部位之DNA序列。 SEQ ID NO: 3 is a DNA sequence of a protein expression site amplified by using the primers of SEQ ID Nos. 1 and 2 in such a manner as to express human tachykinin receptor 1.

<110> Kissei藥品工業股份有限公司 <110> Kissei Pharmaceutical Industry Co., Ltd.

<120> 羧甲基哌啶衍生物 <120> Carboxymethyl piperidine derivatives

<130> JP-A1414-TW <130> JP-A1414-TW

<150> JP2013-231773 <150> JP2013-231773

<151> 2013/11/08 <151> 2013/11/08

<160> 3 <160> 3

<170> PatentIn第3.5版 <170> PatentIn version 3.5

<210> 1 <210> 1

<211> 28 <211> 28

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 前置引子 <223> Pre-introduction

<400> 1 <400> 1

<210> 2 <210> 2

<211> 28 <211> 28

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 反置引子 <223> Inverse primer

<400> 2 <400> 2

<210> 3 <210> 3

<211> 1224 <211> 1224

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 3 <400> 3

Claims (12)

一種化合物或其藥理學上容許之鹽，該化合物係以式(I)表示： [式中，環A為式： 所表示之基；環B為式： 所表示之基；(其中，標記(＊)之鍵為與式： 之鍵結部位；標記(＊＊)之鍵為與環A之鍵結部位；標記(＊＊＊)之鍵表示與式：[化5] 之鍵結部位)；R1為C1-6烷基或C1-6烷氧基；R2及R3分別獨立為氫原子或甲基；n為0、1、2、3、4或5]。 A compound or a pharmacologically acceptable salt thereof, which is represented by formula (I): [wherein, ring A is of the formula: The base represented; ring B is of the formula: The base represented; (where the key of the mark (*) is the formula: The bonding part; the key of the mark (**) is the bonding part with the ring A; the key of the mark (***) is expressed by the formula: [Chemical 5] a bonding site); R 1 is a C 1-6 alkyl group or a C 1-6 alkoxy group; and R 2 and R 3 are each independently a hydrogen atom or a methyl group; n is 0, 1, 2, 3, 4 or 5]. 如申請專利範圍第1項之化合物或其藥理學上容許之鹽，其中，該化合物係以式(Ia)表示： [式中，環A、R1、及n為與申請專利範圍第1項相同之含義；環Bb為式： 所表示之基；(式中，標記(＊)之鍵為與式： 之鍵結部位；(＊＊)及(＊＊＊)為與申請專利範圍第1項相同之含義)]。 The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the compound is represented by the formula (Ia): [wherein, Ring A, R 1 , and n have the same meaning as Item 1 of the scope of the patent application; Ring B b is of the formula: The base represented; (where the key of the mark (*) is the formula: The bonding portion; (**) and (***) have the same meaning as the first item of the patent application scope)]. 如申請專利範圍第2項之化合物或其藥理學上容許之鹽，其中，該化合物係以式(Ib)表示： [式中，環A及環Bb為與申請專利範圍第2項相同之含義；(其中，標記(＊)之鍵為與式： 之鍵結部位；(＊＊)及(＊＊＊)為與申請專利範圍第2項相同之含義)；R1a、R1b、R1c、R1d及R1e分別獨立為氫原子、甲基或甲氧基]。 The compound of claim 2 or a pharmacologically acceptable salt thereof, wherein the compound is represented by the formula (Ib): [wherein, ring A and ring B b have the same meaning as item 2 of the scope of the patent application; (wherein the key of the mark (*) is the formula: The bonding sites; (**) and (***) have the same meaning as the second item of the patent application; R 1a , R 1b , R 1c , R 1d and R 1e are each independently a hydrogen atom or a methyl group. Or methoxy]. 如申請專利範圍第1項之化合物或其藥理學上容許之鹽，其中，環B係以下述式表示： (式中，(＊)、(＊＊)及(＊＊＊)為與申請專利範圍第1項相同之含義)。 The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the ring B is represented by the following formula: (wherein, (*), (**), and (***) have the same meaning as item 1 of the scope of patent application). 如申請專利範圍第4項之化合物或其藥理學上容許之鹽，其中，R1為甲基，且n為0或1。 A compound according to claim 4 or a pharmacologically acceptable salt thereof, wherein R 1 is a methyl group and n is 0 or 1. 一種化合物或其藥理學上容許之鹽，該化合物係以下述式表示： A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula: 一種化合物或其藥理學上容許之鹽，該化合物係以下述式表示： A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula: 一種化合物或其藥理學上容許之鹽，該化合物係以下述式表示： A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula: 一種化合物或其藥理學上容許之鹽，該化合物係以下述式表示：[化15] A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula: [Chem. 15] 一種化合物或其藥理學上容許之鹽，該化合物係以下述式表示： A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula: 一種醫藥組成物，其含有申請專利範圍第1至10項中任一項之化合物或其藥理學上容許之鹽作為有效成分。 A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmacologically acceptable salt thereof as an active ingredient. 如申請專利範圍第11項之醫藥組成物，其係用於預防伴隨抗惡性腫瘤劑投予所產生之噁心及嘔吐之醫藥組成物。 A pharmaceutical composition according to claim 11 which is a pharmaceutical composition for preventing nausea and vomiting caused by administration of an anti-malignant agent.
TW103138516A 2013-11-08 2014-11-06 Carboxymethylpiperidine derivative TWI657082B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2013-231773 2013-11-08
JP2013231773 2013-11-08

Publications (2)

Publication Number Publication Date
TW201605823A true TW201605823A (en) 2016-02-16
TWI657082B TWI657082B (en) 2019-04-21

Family

ID=53041521

Family Applications (1)

Application Number Title Priority Date Filing Date
TW103138516A TWI657082B (en) 2013-11-08 2014-11-06 Carboxymethylpiperidine derivative

Country Status (15)

Country Link
US (1) US10100030B2 (en)
EP (1) EP3067349B1 (en)
JP (1) JP5806420B1 (en)
KR (1) KR20160078997A (en)
CN (1) CN105745198B (en)
AU (1) AU2014347644B2 (en)
BR (1) BR112016009811A2 (en)
CA (1) CA2930008A1 (en)
ES (1) ES2671418T3 (en)
IL (1) IL245286B (en)
MX (1) MX368070B (en)
PL (1) PL3067349T3 (en)
RU (1) RU2673084C2 (en)
TW (1) TWI657082B (en)
WO (1) WO2015068744A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI649307B (en) * 2014-05-07 2019-02-01 日商橘生藥品工業股份有限公司 Cyclohexylpyridine derivative
WO2016021562A1 (en) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Cyanothiophene derivative
US10399949B2 (en) 2015-12-07 2019-09-03 Kissei Pharmaceutical Co., Ltd. NK1 receptor antagonist
KR102351942B1 (en) 2016-06-21 2022-01-18 디아이씨 가부시끼가이샤 Alcohol-modified polyamideimide resin and manufacturing method thereof
JP2023501666A (en) 2019-11-15 2023-01-18 カンディー セラピューティクス リミテッド A Novel Chemical Method for Making 6-Chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine, a Key Intermediate of NT-814

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE277905T1 (en) * 1999-02-24 2004-10-15 Hoffmann La Roche 4-PHENYLPYRIDINE DERIVATIVES AND THEIR USE AS NK-1 RECEPTOR ANTAGONISTS
AU772446B2 (en) 1999-02-24 2004-04-29 F. Hoffmann-La Roche Ag 3-phenylpyridine derivatives and their use as NK-1 receptor antagonists
ES2208205T3 (en) 1999-11-29 2004-06-16 F. Hoffmann-La Roche Ag 2- (3,5-BIS-TRIFLUOROMETIL-PHENYL) -N-METIL-N- (6-MORFOLIN-4-IL-4-OTOLIL-PIRIDIN-3-IL) -ISOBUTIRAMIDA.
CZ303639B6 (en) 2000-07-14 2013-01-23 F. Hoffmann-La Roche Ag N-oxide of 4-phenyl pyridine derivative, process for its preparation and medicament in which the derivative is comprised
TWI287003B (en) 2000-07-24 2007-09-21 Hoffmann La Roche 4-phenyl-pyridine derivatives
TWI259180B (en) * 2000-08-08 2006-08-01 Hoffmann La Roche 4-Phenyl-pyridine derivatives
CA2444395C (en) 2001-04-23 2010-12-21 F. Hoffmann-La Roche Ag Use of nk-1 receptor antagonists against benign prostatic hyperplasia
US20030083345A1 (en) 2001-07-10 2003-05-01 Torsten Hoffmann Method of treatment and/or prevention of brain, spinal or nerve injury
US6849624B2 (en) 2001-07-31 2005-02-01 Hoffmann-La Roche Inc. Aromatic and heteroaromatic substituted amides
CA2530886C (en) 2003-07-03 2013-05-28 F. Hoffmann-La Roche Ag Dual nk1/nk3 antagonists for treating schizophrenia
US20060030600A1 (en) 2004-08-06 2006-02-09 Patrick Schnider Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia
ES2320590T3 (en) 2005-03-23 2009-05-25 F. Hoffmann-La Roche Ag METABOLITES FOR ANTAGONISTS NK-1 FOR EMESIS.
EP1928886B1 (en) 2005-09-09 2011-04-13 GlaxoSmithKline LLC Pyridine derivatives and their use in the treatment of psychotic disorders
ES2335922T3 (en) 2005-09-23 2010-04-06 F.Hoffmann-La Roche Ag NEW DOSAGE FORMULATION.
AR060403A1 (en) * 2006-04-12 2008-06-11 Sanofi Aventis AMINO COMPOUNDS- PYRIMIDINE 2.6- SUBSTITUTES -4- MONOSUSTITUTES AS ANTAGONISTS OF PROSTAGLANDINA D2 RECEIVER
EP2061460A2 (en) * 2006-08-07 2009-05-27 Albany Molecular Research, Inc. 2-aminobenzoxazole carboxamides as 5ht3 modulators
GB0808747D0 (en) 2008-05-14 2008-06-18 Glaxo Wellcome Mfg Pte Ltd Novel compounds
WO2011054773A1 (en) 2009-11-03 2011-05-12 Glaxosmithkline Llc Novel lactam compounds
US8426450B1 (en) 2011-11-29 2013-04-23 Helsinn Healthcare Sa Substituted 4-phenyl pyridines having anti-emetic effect

Also Published As

Publication number Publication date
BR112016009811A2 (en) 2017-12-05
CN105745198A (en) 2016-07-06
AU2014347644A1 (en) 2016-05-19
AU2014347644B2 (en) 2018-06-14
RU2016122464A3 (en) 2018-06-25
IL245286A0 (en) 2016-06-30
TWI657082B (en) 2019-04-21
WO2015068744A1 (en) 2015-05-14
KR20160078997A (en) 2016-07-05
EP3067349B1 (en) 2018-02-28
MX368070B (en) 2019-09-18
JPWO2015068744A1 (en) 2017-03-09
CN105745198B (en) 2018-09-21
US20160289206A1 (en) 2016-10-06
EP3067349A4 (en) 2016-12-28
ES2671418T3 (en) 2018-06-06
RU2016122464A (en) 2017-12-11
MX2016006004A (en) 2016-08-12
EP3067349A1 (en) 2016-09-14
RU2673084C2 (en) 2018-11-22
JP5806420B1 (en) 2015-11-10
PL3067349T3 (en) 2018-06-29
IL245286B (en) 2019-09-26
US10100030B2 (en) 2018-10-16
CA2930008A1 (en) 2015-05-14

Similar Documents

Publication Publication Date Title
KR20210098960A (en) HELIOS small molecule degrading agent and method of use
TWI657082B (en) Carboxymethylpiperidine derivative
US10011568B2 (en) Cyclohexyl pyridine derivative
JP6609253B2 (en) Cyanothiophene derivatives
US10399949B2 (en) NK1 receptor antagonist
NZ726027B2 (en) Cyclohexyl pyridine derivative

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees